Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element
Identifieur interne : 000459 ( Pmc/Checkpoint ); précédent : 000458; suivant : 000460Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element
Auteurs : Anushka C. Galasiti Kankanamalage [États-Unis] ; Yunjeong Kim [États-Unis] ; Vishnu C. Damalanka [États-Unis] ; Athri D. Rathnayake [États-Unis] ; Anthony R. Fehr [États-Unis] ; Nurjahan Mehzabeen [États-Unis] ; Kevin P. Battaile [États-Unis] ; Scott Lovell [États-Unis] ; Gerald H. Lushington [États-Unis] ; Stanley Perlman [États-Unis] ; Kyeong-Ok Chang [États-Unis] ; William C. Groutas [États-Unis]Source :
- European Journal of Medicinal Chemistry [ 0223-5234 ] ; 2018.
Abstract
There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.
Url:
DOI: 10.1016/j.ejmech.2018.03.004
PubMed: 29544147
PubMed Central: 5891363
Affiliations:
- États-Unis
- Illinois, Iowa, Kansas
- Iowa City, Lawrence (Kansas)
- Université de l'Iowa, Université du Kansas
Links toward previous steps (curation, corpus...)
Links to Exploration step
PMC:5891363Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element</title><author><name sortKey="Galasiti Kankanamalage, Anushka C" sort="Galasiti Kankanamalage, Anushka C" uniqKey="Galasiti Kankanamalage A" first="Anushka C." last="Galasiti Kankanamalage">Anushka C. Galasiti Kankanamalage</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Kim, Yunjeong" sort="Kim, Yunjeong" uniqKey="Kim Y" first="Yunjeong" last="Kim">Yunjeong Kim</name><affiliation wicri:level="2"><nlm:aff id="aff2">Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Damalanka, Vishnu C" sort="Damalanka, Vishnu C" uniqKey="Damalanka V" first="Vishnu C." last="Damalanka">Vishnu C. Damalanka</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Rathnayake, Athri D" sort="Rathnayake, Athri D" uniqKey="Rathnayake A" first="Athri D." last="Rathnayake">Athri D. Rathnayake</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Fehr, Anthony R" sort="Fehr, Anthony R" uniqKey="Fehr A" first="Anthony R." last="Fehr">Anthony R. Fehr</name><affiliation wicri:level="4"><nlm:aff id="aff6">Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Mehzabeen, Nurjahan" sort="Mehzabeen, Nurjahan" uniqKey="Mehzabeen N" first="Nurjahan" last="Mehzabeen">Nurjahan Mehzabeen</name><affiliation wicri:level="4"><nlm:aff id="aff3">Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047</wicri:regionArea><placeName><region type="state">Kansas</region><settlement type="city">Lawrence (Kansas)</settlement></placeName><orgName type="university">Université du Kansas</orgName></affiliation></author><author><name sortKey="Battaile, Kevin P" sort="Battaile, Kevin P" uniqKey="Battaile K" first="Kevin P." last="Battaile">Kevin P. Battaile</name><affiliation wicri:level="2"><nlm:aff id="aff4">IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, IL 60439, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, IL 60439</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Lovell, Scott" sort="Lovell, Scott" uniqKey="Lovell S" first="Scott" last="Lovell">Scott Lovell</name><affiliation wicri:level="4"><nlm:aff id="aff3">Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047</wicri:regionArea><placeName><region type="state">Kansas</region><settlement type="city">Lawrence (Kansas)</settlement></placeName><orgName type="university">Université du Kansas</orgName></affiliation></author><author><name sortKey="Lushington, Gerald H" sort="Lushington, Gerald H" uniqKey="Lushington G" first="Gerald H." last="Lushington">Gerald H. Lushington</name><affiliation wicri:level="2"><nlm:aff id="aff5">LiS Consulting, Lawrence, KS 66046, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>LiS Consulting, Lawrence, KS 66046</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation wicri:level="4"><nlm:aff id="aff6">Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Chang, Kyeong Ok" sort="Chang, Kyeong Ok" uniqKey="Chang K" first="Kyeong-Ok" last="Chang">Kyeong-Ok Chang</name><affiliation wicri:level="2"><nlm:aff id="aff2">Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Groutas, William C" sort="Groutas, William C" uniqKey="Groutas W" first="William C." last="Groutas">William C. Groutas</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29544147</idno><idno type="pmc">5891363</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891363</idno><idno type="RBID">PMC:5891363</idno><idno type="doi">10.1016/j.ejmech.2018.03.004</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000C57</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C57</idno><idno type="wicri:Area/Pmc/Curation">000C57</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000C57</idno><idno type="wicri:Area/Pmc/Checkpoint">000459</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000459</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element</title><author><name sortKey="Galasiti Kankanamalage, Anushka C" sort="Galasiti Kankanamalage, Anushka C" uniqKey="Galasiti Kankanamalage A" first="Anushka C." last="Galasiti Kankanamalage">Anushka C. Galasiti Kankanamalage</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Kim, Yunjeong" sort="Kim, Yunjeong" uniqKey="Kim Y" first="Yunjeong" last="Kim">Yunjeong Kim</name><affiliation wicri:level="2"><nlm:aff id="aff2">Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Damalanka, Vishnu C" sort="Damalanka, Vishnu C" uniqKey="Damalanka V" first="Vishnu C." last="Damalanka">Vishnu C. Damalanka</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Rathnayake, Athri D" sort="Rathnayake, Athri D" uniqKey="Rathnayake A" first="Athri D." last="Rathnayake">Athri D. Rathnayake</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Fehr, Anthony R" sort="Fehr, Anthony R" uniqKey="Fehr A" first="Anthony R." last="Fehr">Anthony R. Fehr</name><affiliation wicri:level="4"><nlm:aff id="aff6">Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Mehzabeen, Nurjahan" sort="Mehzabeen, Nurjahan" uniqKey="Mehzabeen N" first="Nurjahan" last="Mehzabeen">Nurjahan Mehzabeen</name><affiliation wicri:level="4"><nlm:aff id="aff3">Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047</wicri:regionArea><placeName><region type="state">Kansas</region><settlement type="city">Lawrence (Kansas)</settlement></placeName><orgName type="university">Université du Kansas</orgName></affiliation></author><author><name sortKey="Battaile, Kevin P" sort="Battaile, Kevin P" uniqKey="Battaile K" first="Kevin P." last="Battaile">Kevin P. Battaile</name><affiliation wicri:level="2"><nlm:aff id="aff4">IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, IL 60439, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, IL 60439</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Lovell, Scott" sort="Lovell, Scott" uniqKey="Lovell S" first="Scott" last="Lovell">Scott Lovell</name><affiliation wicri:level="4"><nlm:aff id="aff3">Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047</wicri:regionArea><placeName><region type="state">Kansas</region><settlement type="city">Lawrence (Kansas)</settlement></placeName><orgName type="university">Université du Kansas</orgName></affiliation></author><author><name sortKey="Lushington, Gerald H" sort="Lushington, Gerald H" uniqKey="Lushington G" first="Gerald H." last="Lushington">Gerald H. Lushington</name><affiliation wicri:level="2"><nlm:aff id="aff5">LiS Consulting, Lawrence, KS 66046, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>LiS Consulting, Lawrence, KS 66046</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation wicri:level="4"><nlm:aff id="aff6">Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Chang, Kyeong Ok" sort="Chang, Kyeong Ok" uniqKey="Chang K" first="Kyeong-Ok" last="Chang">Kyeong-Ok Chang</name><affiliation wicri:level="2"><nlm:aff id="aff2">Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author><author><name sortKey="Groutas, William C" sort="Groutas, William C" uniqKey="Groutas W" first="William C." last="Groutas">William C. Groutas</name><affiliation wicri:level="2"><nlm:aff id="aff1">Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, Wichita State University, Wichita, KS 67260</wicri:regionArea><placeName><region type="state">Kansas</region></placeName></affiliation></author></analytic><series><title level="j">European Journal of Medicinal Chemistry</title><idno type="ISSN">0223-5234</idno><idno type="eISSN">1768-3254</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Masters, P S" uniqKey="Masters P">P.S. Masters</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coleman, C M" uniqKey="Coleman C">C.M. Coleman</name></author><author><name sortKey="Frieman, M B" uniqKey="Frieman M">M.B. Frieman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wit, E" uniqKey="De Wit E">E. De Wit</name></author><author><name sortKey="Van Doremalen, N" uniqKey="Van Doremalen N">N. van Doremalen</name></author><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D. Falzarano</name></author><author><name sortKey="Munster, V J" uniqKey="Munster V">V.J. Munster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Greenberg, S B" uniqKey="Greenberg S">S.B. Greenberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vijay, R" uniqKey="Vijay R">R. Vijay</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Den Brand, J M A" uniqKey="Van Den Brand J">J.M.A. Van den Brand</name></author><author><name sortKey="Smits, S L" uniqKey="Smits S">S.L. Smits</name></author><author><name sortKey="Haagmans, B L" uniqKey="Haagmans B">B.L. Haagmans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, J F W" uniqKey="Chan J">J.F.W. Chan</name></author><author><name sortKey="Lau, S K P" uniqKey="Lau S">S.K.P. Lau</name></author><author><name sortKey="To, K K W" uniqKey="To K">K.K.W. To</name></author><author><name sortKey="Cheng, V C C" uniqKey="Cheng V">V.C.C. Cheng</name></author><author><name sortKey="Woo, P C Y" uniqKey="Woo P">P.C.Y. Woo</name></author><author><name sortKey="Yuen, K Y" uniqKey="Yuen K">K.-Y. Yuen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hui, D S" uniqKey="Hui D">D.S. Hui</name></author><author><name sortKey="Peiris, M" uniqKey="Peiris M">M. Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zumla, A" uniqKey="Zumla A">A. Zumla</name></author><author><name sortKey="Chan, J F" uniqKey="Chan J">J.F. Chan</name></author><author><name sortKey="Azhar, E" uniqKey="Azhar E">E. Azhar</name></author><author><name sortKey="Hui, D S" uniqKey="Hui D">D.S. Hui</name></author><author><name sortKey="Yuen, K Y" uniqKey="Yuen K">K.-Y. Yuen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adedeji, A O" uniqKey="Adedeji A">A.O. Adedeji</name></author><author><name sortKey="Sarafianos, S G" uniqKey="Sarafianos S">S.G. Sarafianos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Modjarrad, K" uniqKey="Modjarrad K">K. Modjarrad</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Qian, Z" uniqKey="Qian Z">Z. Qian</name></author><author><name sortKey="Dominguez, S R" uniqKey="Dominguez S">S.R. Dominguez</name></author><author><name sortKey="Holmes, K V" uniqKey="Holmes K">K.V. Holmes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shirato, K" uniqKey="Shirato K">K. Shirato</name></author><author><name sortKey="Kawase, M" uniqKey="Kawase M">M. Kawase</name></author><author><name sortKey="Matsuyama, S" uniqKey="Matsuyama S">S. Matsuyama</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Miller, J K" uniqKey="Miller J">J.K. Miller</name></author><author><name sortKey="Whittaker, G R" uniqKey="Whittaker G">G.R. Whittaker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pillaiyar, T" uniqKey="Pillaiyar T">T. Pillaiyar</name></author><author><name sortKey="Manickam, M" uniqKey="Manickam M">M. Manickam</name></author><author><name sortKey="Namasivayam, V" uniqKey="Namasivayam V">V. Namasivayam</name></author><author><name sortKey="Hayashi, Y" uniqKey="Hayashi Y">Y. Hayashi</name></author><author><name sortKey="Jung, S H" uniqKey="Jung S">S.-H. Jung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baez Santos, Y M" uniqKey="Baez Santos Y">Y.M. Baez-Santos</name></author><author><name sortKey="St John, S E" uniqKey="St John S">S.E. St. John</name></author><author><name sortKey="Mesecar, A D" uniqKey="Mesecar A">A.D. Mesecar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kumar, V" uniqKey="Kumar V">V. Kumar</name></author><author><name sortKey="Tan, K P" uniqKey="Tan K">K.-P. Tan</name></author><author><name sortKey="Wang, Y M" uniqKey="Wang Y">Y.-M. Wang</name></author><author><name sortKey="Lin, S W" uniqKey="Lin S">S.-W. Lin</name></author><author><name sortKey="Liang, P H" uniqKey="Liang P">P.-H. Liang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Needle, D" uniqKey="Needle D">D. Needle</name></author><author><name sortKey="Lountos, G T" uniqKey="Lountos G">G.T. Lountos</name></author><author><name sortKey="Waugh, D S" uniqKey="Waugh D">D.S. Waugh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hilgenfeld, R" uniqKey="Hilgenfeld R">R. Hilgenfeld</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, A" uniqKey="Wu A">A. Wu</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Zeng, C" uniqKey="Zeng C">C. Zeng</name></author><author><name sortKey="Huang, X" uniqKey="Huang X">X. Huang</name></author><author><name sortKey="Xu, S" uniqKey="Xu S">S. Xu</name></author><author><name sortKey="Su, C" uniqKey="Su C">C. Su</name></author><author><name sortKey="Wang, M" uniqKey="Wang M">M. Wang</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y. Chen</name></author><author><name sortKey="Guo, D" uniqKey="Guo D">D. Guo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, H" uniqKey="Lee H">H. Lee</name></author><author><name sortKey="Lei, H" uniqKey="Lei H">H. Lei</name></author><author><name sortKey="Santarsiero, B D" uniqKey="Santarsiero B">B.D. Santarsiero</name></author><author><name sortKey="Gatuz, J L" uniqKey="Gatuz J">J.L. Gatuz</name></author><author><name sortKey="Cao, S" uniqKey="Cao S">S. Cao</name></author><author><name sortKey="Rice, A J" uniqKey="Rice A">A.J. Rice</name></author><author><name sortKey="Patel, K" uniqKey="Patel K">K. Patel</name></author><author><name sortKey="Szypulinski, M" uniqKey="Szypulinski M">M. Szypulinski</name></author><author><name sortKey="Ojeda, I" uniqKey="Ojeda I">I. Ojeda</name></author><author><name sortKey="Ghosh, A K" uniqKey="Ghosh A">A.K. Ghosh</name></author><author><name sortKey="Johnson, M E" uniqKey="Johnson M">M.E. Johnson</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Wang, F" uniqKey="Wang F">F. Wang</name></author><author><name sortKey="Chen, C" uniqKey="Chen C">C. Chen</name></author><author><name sortKey="Tan, W" uniqKey="Tan W">W. Tan</name></author><author><name sortKey="Yang, K" uniqKey="Yang K">K. Yang</name></author><author><name sortKey="Yang, H" uniqKey="Yang H">H. Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y. Kim</name></author><author><name sortKey="Liu, H" uniqKey="Liu H">H. Liu</name></author><author><name sortKey="Galasiti Kankanamalage, A C" uniqKey="Galasiti Kankanamalage A">A.C. Galasiti Kankanamalage</name></author><author><name sortKey="Weerasekara, S" uniqKey="Weerasekara S">S. Weerasekara</name></author><author><name sortKey="Hua, D H" uniqKey="Hua D">D.H. Hua</name></author><author><name sortKey="Groutas, W C" uniqKey="Groutas W">W.C. Groutas</name></author><author><name sortKey="Chang, K O" uniqKey="Chang K">K.O. Chang</name></author><author><name sortKey="Pedersen, N C" uniqKey="Pedersen N">N.C. Pedersen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pedersen, N C" uniqKey="Pedersen N">N.C. Pedersen</name></author><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y. Kim</name></author><author><name sortKey="Liu, H" uniqKey="Liu H">H. Liu</name></author><author><name sortKey="Galasiti Kankanamalage, A C" uniqKey="Galasiti Kankanamalage A">A.C. Galasiti Kankanamalage</name></author><author><name sortKey="Eckstrand, C" uniqKey="Eckstrand C">C. Eckstrand</name></author><author><name sortKey="Groutas, W C" uniqKey="Groutas W">W.C. Groutas</name></author><author><name sortKey="Bannasch, M" uniqKey="Bannasch M">M. Bannasch</name></author><author><name sortKey="Meadows, J M" uniqKey="Meadows J">J.M. Meadows</name></author><author><name sortKey="Chang, K O" uniqKey="Chang K">K.O. Chang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Webster, S E" uniqKey="Webster S">S.E. Webster</name></author><author><name sortKey="Okano, K" uniqKey="Okano K">K. Okano</name></author><author><name sortKey="Little, T L" uniqKey="Little T">T.L. Little</name></author><author><name sortKey="Reich, S H" uniqKey="Reich S">S.H. Reich</name></author><author><name sortKey="Xin, Y" uniqKey="Xin Y">Y. Xin</name></author><author><name sortKey="Fuhrman, S A" uniqKey="Fuhrman S">S.A. Fuhrman</name></author><author><name sortKey="Matthews, D A" uniqKey="Matthews D">D.A. Matthews</name></author><author><name sortKey="Love, R A" uniqKey="Love R">R.A. Love</name></author><author><name sortKey="Hendrickson, T F" uniqKey="Hendrickson T">T.F. Hendrickson</name></author><author><name sortKey="Patick, A K" uniqKey="Patick A">A.K. Patick</name></author><author><name sortKey="Meador, J W" uniqKey="Meador J">J.W. Meador</name></author><author><name sortKey="Ferre, R A" uniqKey="Ferre R">R.A. Ferre</name></author><author><name sortKey="Brown, E L" uniqKey="Brown E">E.L. Brown</name></author><author><name sortKey="Ford, C E" uniqKey="Ford C">C.E. Ford</name></author><author><name sortKey="Binford, S L" uniqKey="Binford S">S.L. Binford</name></author><author><name sortKey="Worland, S T" uniqKey="Worland S">S.T. Worland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Galasiti Kankanamalage, A C" uniqKey="Galasiti Kankanamalage A">A.C. Galasiti Kankanamalage</name></author><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y. Kim</name></author><author><name sortKey="Weerawarna, P W" uniqKey="Weerawarna P">P.W. Weerawarna</name></author><author><name sortKey="Uy, R A Z" uniqKey="Uy R">R.A.Z. Uy</name></author><author><name sortKey="Damalanka, V C" uniqKey="Damalanka V">V.C. Damalanka</name></author><author><name sortKey="Mndadapu, S R" uniqKey="Mndadapu S">S.R. Mndadapu</name></author><author><name sortKey="Alliston, K R" uniqKey="Alliston K">K.R. Alliston</name></author><author><name sortKey="Mehzabeen, N" uniqKey="Mehzabeen N">N. Mehzabeen</name></author><author><name sortKey="Battaille, K P" uniqKey="Battaille K">K.P. Battaille</name></author><author><name sortKey="Lovell, S" uniqKey="Lovell S">S. Lovell</name></author><author><name sortKey="Chang, K O" uniqKey="Chang K">K.-O. Chang</name></author><author><name sortKey="Groutas, W C" uniqKey="Groutas W">W.C. Groutas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mandadapu, S R" uniqKey="Mandadapu S">S.R. Mandadapu</name></author><author><name sortKey="Gunnam, M R" uniqKey="Gunnam M">M.R. Gunnam</name></author><author><name sortKey="Tiew, K C" uniqKey="Tiew K">K.-C. Tiew</name></author><author><name sortKey="Uy, R A Z" uniqKey="Uy R">R.A.Z. Uy</name></author><author><name sortKey="Prior, A M" uniqKey="Prior A">A.M. Prior</name></author><author><name sortKey="Alliston, K R" uniqKey="Alliston K">K.R. Alliston</name></author><author><name sortKey="Hua, D H" uniqKey="Hua D">D.H. Hua</name></author><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y. Kim</name></author><author><name sortKey="Chang, K O" uniqKey="Chang K">K.-O. Chang</name></author><author><name sortKey="Groutas, W C" uniqKey="Groutas W">W.C. Groutas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y. Kim</name></author><author><name sortKey="Lovell, S" uniqKey="Lovell S">S. Lovell</name></author><author><name sortKey="Tiew, K C" uniqKey="Tiew K">K.C. Tiew</name></author><author><name sortKey="Mandadapu, S R" uniqKey="Mandadapu S">S.R. Mandadapu</name></author><author><name sortKey="Alliston, K R" uniqKey="Alliston K">K.R. Alliston</name></author><author><name sortKey="Battaille, K P" uniqKey="Battaille K">K.P. Battaille</name></author><author><name sortKey="Groutas, W C" uniqKey="Groutas W">W.C. Groutas</name></author><author><name sortKey="Chang, K O" uniqKey="Chang K">K.-O. Chang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wilde, A H" uniqKey="De Wilde A">A.H. de Wilde</name></author><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D. Falzarano</name></author><author><name sortKey="Zevenhoven Dobbe, J C" uniqKey="Zevenhoven Dobbe J">J.C. Zevenhoven-Dobbe</name></author><author><name sortKey="Beugeling, C" uniqKey="Beugeling C">C. Beugeling</name></author><author><name sortKey="Fett, C" uniqKey="Fett C">C. Fett</name></author><author><name sortKey="Martellaro, C" uniqKey="Martellaro C">C. Martellaro</name></author><author><name sortKey="Posthuma, C C" uniqKey="Posthuma C">C.C. Posthuma</name></author><author><name sortKey="Feldmann, H" uniqKey="Feldmann H">H. Feldmann</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S. Perlman</name></author><author><name sortKey="Snijder, E J" uniqKey="Snijder E">E.J. Snijder</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Kabsch, W" uniqKey="Kabsch W">W. Kabsch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kabsch, W" uniqKey="Kabsch W">W. Kabsch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vonrhein, C" uniqKey="Vonrhein C">C. Vonrhein</name></author><author><name sortKey="Flensburg, C" uniqKey="Flensburg C">C. Flensburg</name></author><author><name sortKey="Keller, P" uniqKey="Keller P">P. Keller</name></author><author><name sortKey="Sharff, A" uniqKey="Sharff A">A. Sharff</name></author><author><name sortKey="Smart, O" uniqKey="Smart O">O. Smart</name></author><author><name sortKey="Paciorek, W" uniqKey="Paciorek W">W. Paciorek</name></author><author><name sortKey="Womack, T" uniqKey="Womack T">T. Womack</name></author><author><name sortKey="Bricogne, G" uniqKey="Bricogne G">G. Bricogne</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Evans, P R" uniqKey="Evans P">P.R. Evans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccoy, A J" uniqKey="Mccoy A">A.J. McCoy</name></author><author><name sortKey="Grosse Kunstleve, R W" uniqKey="Grosse Kunstleve R">R.W. Grosse-Kunstleve</name></author><author><name sortKey="Adams, P D" uniqKey="Adams P">P.D. Adams</name></author><author><name sortKey="Winn, M" uniqKey="Winn M">M. Winn</name></author><author><name sortKey="Storoni, L C" uniqKey="Storoni L">L.C. Storoni</name></author><author><name sortKey="Read, R J" uniqKey="Read R">R.J. Read</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnston, T S" uniqKey="Johnston T">T.S. Johnston</name></author><author><name sortKey="St John, S E" uniqKey="St John S">S.E. St. John</name></author><author><name sortKey="Osswald, H L" uniqKey="Osswald H">H.L. Osswald</name></author><author><name sortKey="Nyalapatla, P R" uniqKey="Nyalapatla P">P.R. Nyalapatla</name></author><author><name sortKey="Paul, L N" uniqKey="Paul L">L.N. Paul</name></author><author><name sortKey="Ghosh, A K" uniqKey="Ghosh A">A.K. Ghosh</name></author><author><name sortKey="Denison, M R" uniqKey="Denison M">M.R. Denison</name></author><author><name sortKey="Mesecar, A D" uniqKey="Mesecar A">A.D. Mesecar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adams, P D" uniqKey="Adams P">P.D. Adams</name></author><author><name sortKey="Afonine, P V" uniqKey="Afonine P">P.V. Afonine</name></author><author><name sortKey="Bunkoczi, G" uniqKey="Bunkoczi G">G. Bunkoczi</name></author><author><name sortKey="Chen, V B" uniqKey="Chen V">V.B. Chen</name></author><author><name sortKey="David, I W" uniqKey="David I">I.W. David</name></author><author><name sortKey="Echols, N" uniqKey="Echols N">N. Echols</name></author><author><name sortKey="Headd, J J" uniqKey="Headd J">J.J. Headd</name></author><author><name sortKey="Hung, L W" uniqKey="Hung L">L.W. Hung</name></author><author><name sortKey="Kapral, G J" uniqKey="Kapral G">G.J. Kapral</name></author><author><name sortKey="Grosse Kunstleve, R W" uniqKey="Grosse Kunstleve R">R.W. Grosse-Kunstleve</name></author><author><name sortKey="Mccoy, A J" uniqKey="Mccoy A">A.J. McCoy</name></author><author><name sortKey="Moriarty, N W" uniqKey="Moriarty N">N.W. Moriarty</name></author><author><name sortKey="Oeffner, R" uniqKey="Oeffner R">R. Oeffner</name></author><author><name sortKey="Read, R J" uniqKey="Read R">R.J. Read</name></author><author><name sortKey="Richardson, D C" uniqKey="Richardson D">D.C. Richardson</name></author><author><name sortKey="Richardson, J S" uniqKey="Richardson J">J.S. Richardson</name></author><author><name sortKey="Terwilliger, T C" uniqKey="Terwilliger T">T.C. Terwilliger</name></author><author><name sortKey="Zwart, P H" uniqKey="Zwart P">P.H. Zwart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Emsley, P" uniqKey="Emsley P">P. Emsley</name></author><author><name sortKey="Lohkamp, B" uniqKey="Lohkamp B">B. Lohkamp</name></author><author><name sortKey="Scott, W G" uniqKey="Scott W">W.G. Scott</name></author><author><name sortKey="Cowtan, K" uniqKey="Cowtan K">K. Cowtan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, V B" uniqKey="Chen V">V.B. Chen</name></author><author><name sortKey="Arendall, W B" uniqKey="Arendall W">W.B. Arendall</name></author><author><name sortKey="Headd, J J" uniqKey="Headd J">J.J. Headd</name></author><author><name sortKey="Keedy, D A" uniqKey="Keedy D">D.A. Keedy</name></author><author><name sortKey="Immormino, R M" uniqKey="Immormino R">R.M. Immormino</name></author><author><name sortKey="Kapral, G J" uniqKey="Kapral G">G.J. Kapral</name></author><author><name sortKey="Murray, L W" uniqKey="Murray L">L.W. Murray</name></author><author><name sortKey="Richardson, J S" uniqKey="Richardson J">J.S. Richardson</name></author><author><name sortKey="Richardson, D C" uniqKey="Richardson D">D.C. Richardson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Potterton, L" uniqKey="Potterton L">L. Potterton</name></author><author><name sortKey="Mcnicholas, S" uniqKey="Mcnicholas S">S. McNicholas</name></author><author><name sortKey="Krissinel, E" uniqKey="Krissinel E">E. Krissinel</name></author><author><name sortKey="Gruber, J" uniqKey="Gruber J">J. Gruber</name></author><author><name sortKey="Cowlan, K" uniqKey="Cowlan K">K. Cowlan</name></author><author><name sortKey="Emlsey, P" uniqKey="Emlsey P">P. Emlsey</name></author><author><name sortKey="Murshudov, G N" uniqKey="Murshudov G">G.N. Murshudov</name></author><author><name sortKey="Cohen, S" uniqKey="Cohen S">S. Cohen</name></author><author><name sortKey="Perrakis, A" uniqKey="Perrakis A">A. Perrakis</name></author><author><name sortKey="Noble, M" uniqKey="Noble M">M. Noble</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Evans, P" uniqKey="Evans P">P. Evans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Diederichs, K" uniqKey="Diederichs K">K. Diederichs</name></author><author><name sortKey="Karplus, P A" uniqKey="Karplus P">P.A. Karplus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weiss, M S" uniqKey="Weiss M">M.S. Weiss</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karplus, P A" uniqKey="Karplus P">P.A. Karplus</name></author><author><name sortKey="Diederichs, K" uniqKey="Diederichs K">K. Diederichs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Evans, P" uniqKey="Evans P">P. Evans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Afonine, P V" uniqKey="Afonine P">P.V. Afonine</name></author><author><name sortKey="Grosse Kunstleve, R W" uniqKey="Grosse Kunstleve R">R.W. Grosse-Kunstleve</name></author><author><name sortKey="Echols, N" uniqKey="Echols N">N. Echols</name></author><author><name sortKey="Headd, J J" uniqKey="Headd J">J.J. Headd</name></author><author><name sortKey="Moriarty, N W" uniqKey="Moriarty N">N.W. Moriarty</name></author><author><name sortKey="Mustyakimov, N" uniqKey="Mustyakimov N">N. Mustyakimov</name></author><author><name sortKey="Terwilliger, T C" uniqKey="Terwilliger T">T.C. Terwilliger</name></author><author><name sortKey="Urzhumtsev, A" uniqKey="Urzhumtsev A">A. Urzhumtsev</name></author><author><name sortKey="Zwart, P H" uniqKey="Zwart P">P.H. Zwart</name></author><author><name sortKey="Adams, P D" uniqKey="Adams P">P.D. Adams</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Eur J Med Chem</journal-id><journal-id journal-id-type="iso-abbrev">Eur J Med Chem</journal-id><journal-title-group><journal-title>European Journal of Medicinal Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0223-5234</issn><issn pub-type="epub">1768-3254</issn><publisher><publisher-name>Elsevier Masson SAS.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29544147</article-id><article-id pub-id-type="pmc">5891363</article-id><article-id pub-id-type="publisher-id">S0223-5234(18)30239-3</article-id><article-id pub-id-type="doi">10.1016/j.ejmech.2018.03.004</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element</article-title></title-group><contrib-group><contrib contrib-type="author" id="au1"><name><surname>Galasiti Kankanamalage</surname><given-names>Anushka C.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au2"><name><surname>Kim</surname><given-names>Yunjeong</given-names></name><xref rid="aff2" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au3"><name><surname>Damalanka</surname><given-names>Vishnu C.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au4"><name><surname>Rathnayake</surname><given-names>Athri D.</given-names></name><xref rid="aff1" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au5"><name><surname>Fehr</surname><given-names>Anthony R.</given-names></name><xref rid="aff6" ref-type="aff">f</xref></contrib><contrib contrib-type="author" id="au6"><name><surname>Mehzabeen</surname><given-names>Nurjahan</given-names></name><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au7"><name><surname>Battaile</surname><given-names>Kevin P.</given-names></name><xref rid="aff4" ref-type="aff">d</xref></contrib><contrib contrib-type="author" id="au8"><name><surname>Lovell</surname><given-names>Scott</given-names></name><xref rid="aff3" ref-type="aff">c</xref></contrib><contrib contrib-type="author" id="au9"><name><surname>Lushington</surname><given-names>Gerald H.</given-names></name><xref rid="aff5" ref-type="aff">e</xref></contrib><contrib contrib-type="author" id="au10"><name><surname>Perlman</surname><given-names>Stanley</given-names></name><xref rid="aff6" ref-type="aff">f</xref></contrib><contrib contrib-type="author" id="au11"><name><surname>Chang</surname><given-names>Kyeong-Ok</given-names></name><email>kchang@vet.ksu.edu</email><xref rid="aff2" ref-type="aff">b</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib><contrib contrib-type="author" id="au12"><name><surname>Groutas</surname><given-names>William C.</given-names></name><email>bill.groutas@wichita.edu</email><xref rid="aff1" ref-type="aff">a</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>a</label>Department of Chemistry, Wichita State University, Wichita, KS 67260, USA</aff><aff id="aff2"><label>b</label>Department of Diagnostic Medicine & Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA</aff><aff id="aff3"><label>c</label>Protein Structure Laboratory, The University of Kansas, Lawrence, KS 66047, USA</aff><aff id="aff4"><label>d</label>IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, IL 60439, USA</aff><aff id="aff5"><label>e</label>LiS Consulting, Lawrence, KS 66046, USA</aff><aff id="aff6"><label>f</label>Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. <email>bill.groutas@wichita.edu</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author. <email>kchang@vet.ksu.edu</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>6</day><month>3</month><year>2018</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><day>25</day><month>4</month><year>2018</year></pub-date><pub-date pub-type="epub"><day>6</day><month>3</month><year>2018</year></pub-date><volume>150</volume><fpage>334</fpage><lpage>346</lpage><history><date date-type="received"><day>7</day><month>10</month><year>2017</year></date><date date-type="rev-recd"><day>28</day><month>2</month><year>2018</year></date><date date-type="accepted"><day>1</day><month>3</month><year>2018</year></date></history><permissions><copyright-statement>© 2018 Elsevier Masson SAS. All rights reserved.</copyright-statement><copyright-year>2018</copyright-year><copyright-holder>Elsevier Masson SAS</copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract id="abs0010"><p>There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.</p></abstract><abstract abstract-type="graphical" id="abs0015"><title>Graphical abstract</title><p><fig id="undfig1" position="anchor"><alt-text id="alttext0010">Image 1</alt-text><graphic xlink:href="fx1_lrg"></graphic></fig></p></abstract><abstract abstract-type="author-highlights" id="abs0020"><title>Highlights</title><p><list list-type="simple" id="ulist0010"><list-item id="u0010"><label>•</label><p id="p0010">The structure-guided design of a new class of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) 3CL protease inhibitors was performed.</p></list-item><list-item id="u0015"><label>•</label><p id="p0015">A piperidine moiety was used as a design element in the synthesis of peptidomimetic inhibitors that exploit interactions with the enzyme S<sub>3</sub>-S<sub>4</sub> subsites.</p></list-item><list-item id="u0020"><label>•</label><p id="p0020">The inhibitor design rationale was validated by X-ray crystallographic studies.</p></list-item><list-item id="u0025"><label>•</label><p id="p0025">X-ray crystallography confirmed the mechanism of action of the inhibitors.</p></list-item></list></p></abstract><kwd-group id="kwrds0010"><title>Keywords</title><kwd>MERS-CoV</kwd><kwd>3CL protease</kwd><kwd>Piperidine moiety</kwd><kwd>Antiviral</kwd><kwd>Peptidomimetic inhibitors</kwd></kwd-group></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Illinois</li><li>Iowa</li><li>Kansas</li></region><settlement><li>Iowa City</li><li>Lawrence (Kansas)</li></settlement><orgName><li>Université de l'Iowa</li><li>Université du Kansas</li></orgName></list><tree><country name="États-Unis"><region name="Kansas"><name sortKey="Galasiti Kankanamalage, Anushka C" sort="Galasiti Kankanamalage, Anushka C" uniqKey="Galasiti Kankanamalage A" first="Anushka C." last="Galasiti Kankanamalage">Anushka C. Galasiti Kankanamalage</name></region><name sortKey="Battaile, Kevin P" sort="Battaile, Kevin P" uniqKey="Battaile K" first="Kevin P." last="Battaile">Kevin P. Battaile</name><name sortKey="Chang, Kyeong Ok" sort="Chang, Kyeong Ok" uniqKey="Chang K" first="Kyeong-Ok" last="Chang">Kyeong-Ok Chang</name><name sortKey="Damalanka, Vishnu C" sort="Damalanka, Vishnu C" uniqKey="Damalanka V" first="Vishnu C." last="Damalanka">Vishnu C. Damalanka</name><name sortKey="Fehr, Anthony R" sort="Fehr, Anthony R" uniqKey="Fehr A" first="Anthony R." last="Fehr">Anthony R. Fehr</name><name sortKey="Groutas, William C" sort="Groutas, William C" uniqKey="Groutas W" first="William C." last="Groutas">William C. Groutas</name><name sortKey="Kim, Yunjeong" sort="Kim, Yunjeong" uniqKey="Kim Y" first="Yunjeong" last="Kim">Yunjeong Kim</name><name sortKey="Lovell, Scott" sort="Lovell, Scott" uniqKey="Lovell S" first="Scott" last="Lovell">Scott Lovell</name><name sortKey="Lushington, Gerald H" sort="Lushington, Gerald H" uniqKey="Lushington G" first="Gerald H." last="Lushington">Gerald H. Lushington</name><name sortKey="Mehzabeen, Nurjahan" sort="Mehzabeen, Nurjahan" uniqKey="Mehzabeen N" first="Nurjahan" last="Mehzabeen">Nurjahan Mehzabeen</name><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><name sortKey="Rathnayake, Athri D" sort="Rathnayake, Athri D" uniqKey="Rathnayake A" first="Athri D." last="Rathnayake">Athri D. Rathnayake</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/MersV1/Data/Pmc/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000459 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd -nk 000459 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= MersV1
|flux= Pmc
|étape= Checkpoint
|type= RBID
|clé= PMC:5891363
|texte= Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/RBID.i -Sk "pubmed:29544147" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd \
| NlmPubMed2Wicri -a MersV1
| This area was generated with Dilib version V0.6.33. |  |