Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.
Identifieur interne : 002F68 ( Ncbi/Checkpoint ); précédent : 002F67; suivant : 002F69Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.
Auteurs : Gaochan Wu [République populaire de Chine] ; Waleed A. Zalloum [Jordanie] ; Megan E. Meuser [États-Unis] ; Lanlan Jing [République populaire de Chine] ; Dongwei Kang [République populaire de Chine] ; Chin-Ho Chen [États-Unis] ; Ye Tian [République populaire de Chine] ; Fangfang Zhang [République populaire de Chine] ; Simon Cocklin [États-Unis] ; Kuo-Hsiung Lee [États-Unis] ; Xinyong Liu [République populaire de Chine] ; Peng Zhan [République populaire de Chine]Source :
- European journal of medicinal chemistry [ 1768-3254 ] ; 2018.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Agents antiVIH (synthèse chimique), Bibliothèques de petites molécules (), Bibliothèques de petites molécules (pharmacologie), Bibliothèques de petites molécules (synthèse chimique), Capside (), Chimie click, Humains, Infections à VIH (traitement médicamenteux), Infections à VIH (virologie), Phénylalanine (analogues et dérivés), Phénylalanine (pharmacologie), Phénylalanine (synthèse chimique), Simulation de dynamique moléculaire, VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
- MESH :
- analogues et dérivés : Phénylalanine.
- pharmacologie : Agents antiVIH, Bibliothèques de petites molécules, Phénylalanine.
- synthèse chimique : Agents antiVIH, Bibliothèques de petites molécules, Phénylalanine.
- traitement médicamenteux : Infections à VIH.
- virologie : Infections à VIH.
- Agents antiVIH, Bibliothèques de petites molécules, Capside, Chimie click, Humains, Simulation de dynamique moléculaire, VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
English descriptors
- KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Capsid (drug effects), Click Chemistry, HIV Infections (drug therapy), HIV Infections (virology), HIV-1 (drug effects), Humans, Molecular Dynamics Simulation, Phenylalanine (analogs & derivatives), Phenylalanine (chemical synthesis), Phenylalanine (pharmacology), Small Molecule Libraries (chemical synthesis), Small Molecule Libraries (chemistry), Small Molecule Libraries (pharmacology).
- MESH :
- chemical , analogs & derivatives : Phenylalanine.
- chemical , chemical synthesis : Anti-HIV Agents, Phenylalanine, Small Molecule Libraries.
- chemical , chemistry : Anti-HIV Agents, Small Molecule Libraries.
- chemical , pharmacology : Anti-HIV Agents, Phenylalanine, Small Molecule Libraries.
- drug effects : Capsid, HIV-1.
- drug therapy : HIV Infections.
- virology : HIV Infections.
- Click Chemistry, Humans, Molecular Dynamics Simulation.
Abstract
The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of HIV-1 replication and is considered an important, clinically unexploited therapeutic target. As such, small drug-like molecules that inhibit this critical HIV-1 protein have become a priority for several groups. Therefore, in this study we explore small molecule targeting of the CA protein, and in particular a very attractive inter-protomer pocket. We report the design, parallel synthesis, and anti-HIV-1 activity evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors synthesized via Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. We demonstrate robust inhibitory activity over a range of potencies against the HIV-1 NL4-3 reference strain. In particular, compound 13m exhibited the greatest potency and lowest toxicity within this new series with an EC50 value of 4.33 μM and CC50 value of >57.74 μM (SI > 13.33). These values are very similar to the lead compound PF-74 (EC50 = 5.95 μM, CC50 > 70.50 μM, SI > 11.85) in our assay, despite significant structural difference. Furthermore, we demonstrate via surface plasmon resonance (SPR) binding assays that 13m interacts robustly with recombinant HIV-1 CA and exhibits antiviral activity in both the early and late stages of HIV-1 replication. Overall, the novel parallel synthesis and structure-activity relationships (SARs) identified within this study set the foundation for further rational optimization and discovery of CA-targeting compounds with improved potency.
DOI: 10.1016/j.ejmech.2018.09.029
PubMed: 30243152
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000974
- to stream PubMed, to step Curation: 000974
- to stream PubMed, to step Checkpoint: 000A13
- to stream Ncbi, to step Merge: 002F68
- to stream Ncbi, to step Curation: 002F68
Links to Exploration step
pubmed:30243152Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.</title><author><name sortKey="Wu, Gaochan" sort="Wu, Gaochan" uniqKey="Wu G" first="Gaochan" last="Wu">Gaochan Wu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Zalloum, Waleed A" sort="Zalloum, Waleed A" uniqKey="Zalloum W" first="Waleed A" last="Zalloum">Waleed A. Zalloum</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821</wicri:regionArea><wicri:noRegion>11821</wicri:noRegion></affiliation></author><author><name sortKey="Meuser, Megan E" sort="Meuser, Megan E" uniqKey="Meuser M" first="Megan E" last="Meuser">Megan E. Meuser</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Jing, Lanlan" sort="Jing, Lanlan" uniqKey="Jing L" first="Lanlan" last="Jing">Lanlan Jing</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Chin Ho" sort="Chen, Chin Ho" uniqKey="Chen C" first="Chin-Ho" last="Chen">Chin-Ho Chen</name><affiliation wicri:level="1"><nlm:affiliation>Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710</wicri:regionArea><wicri:noRegion>27710</wicri:noRegion></affiliation></author><author><name sortKey="Tian, Ye" sort="Tian, Ye" uniqKey="Tian Y" first="Ye" last="Tian">Ye Tian</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Fangfang" sort="Zhang, Fangfang" uniqKey="Zhang F" first="Fangfang" last="Zhang">Fangfang Zhang</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Shandong University, Jinan, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Shandong University, Jinan</wicri:regionArea><wicri:noRegion>Jinan</wicri:noRegion></affiliation></author><author><name sortKey="Cocklin, Simon" sort="Cocklin, Simon" uniqKey="Cocklin S" first="Simon" last="Cocklin">Simon Cocklin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA. Electronic address: sc349@drexel.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Lee, Kuo Hsiung" sort="Lee, Kuo Hsiung" uniqKey="Lee K" first="Kuo-Hsiung" last="Lee">Kuo-Hsiung Lee</name><affiliation wicri:level="1"><nlm:affiliation>Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. Electronic address: khlee@unc.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599</wicri:regionArea><wicri:noRegion>27599</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:30243152</idno><idno type="pmid">30243152</idno><idno type="doi">10.1016/j.ejmech.2018.09.029</idno><idno type="wicri:Area/PubMed/Corpus">000974</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000974</idno><idno type="wicri:Area/PubMed/Curation">000974</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000974</idno><idno type="wicri:Area/PubMed/Checkpoint">000A13</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000A13</idno><idno type="wicri:Area/Ncbi/Merge">002F68</idno><idno type="wicri:Area/Ncbi/Curation">002F68</idno><idno type="wicri:Area/Ncbi/Checkpoint">002F68</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.</title><author><name sortKey="Wu, Gaochan" sort="Wu, Gaochan" uniqKey="Wu G" first="Gaochan" last="Wu">Gaochan Wu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Zalloum, Waleed A" sort="Zalloum, Waleed A" uniqKey="Zalloum W" first="Waleed A" last="Zalloum">Waleed A. Zalloum</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.</nlm:affiliation><country xml:lang="fr">Jordanie</country><wicri:regionArea>Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821</wicri:regionArea><wicri:noRegion>11821</wicri:noRegion></affiliation></author><author><name sortKey="Meuser, Megan E" sort="Meuser, Megan E" uniqKey="Meuser M" first="Megan E" last="Meuser">Megan E. Meuser</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Jing, Lanlan" sort="Jing, Lanlan" uniqKey="Jing L" first="Lanlan" last="Jing">Lanlan Jing</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Chin Ho" sort="Chen, Chin Ho" uniqKey="Chen C" first="Chin-Ho" last="Chen">Chin-Ho Chen</name><affiliation wicri:level="1"><nlm:affiliation>Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710</wicri:regionArea><wicri:noRegion>27710</wicri:noRegion></affiliation></author><author><name sortKey="Tian, Ye" sort="Tian, Ye" uniqKey="Tian Y" first="Ye" last="Tian">Ye Tian</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Fangfang" sort="Zhang, Fangfang" uniqKey="Zhang F" first="Fangfang" last="Zhang">Fangfang Zhang</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Shandong University, Jinan, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Shandong University, Jinan</wicri:regionArea><wicri:noRegion>Jinan</wicri:noRegion></affiliation></author><author><name sortKey="Cocklin, Simon" sort="Cocklin, Simon" uniqKey="Cocklin S" first="Simon" last="Cocklin">Simon Cocklin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA. Electronic address: sc349@drexel.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Lee, Kuo Hsiung" sort="Lee, Kuo Hsiung" uniqKey="Lee K" first="Kuo-Hsiung" last="Lee">Kuo-Hsiung Lee</name><affiliation wicri:level="1"><nlm:affiliation>Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. Electronic address: khlee@unc.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599</wicri:regionArea><wicri:noRegion>27599</wicri:noRegion></affiliation></author><author><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author><author><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong</wicri:regionArea><wicri:noRegion>Shandong</wicri:noRegion></affiliation></author></analytic><series><title level="j">European journal of medicinal chemistry</title><idno type="eISSN">1768-3254</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anti-HIV Agents (chemical synthesis)</term><term>Anti-HIV Agents (chemistry)</term><term>Anti-HIV Agents (pharmacology)</term><term>Capsid (drug effects)</term><term>Click Chemistry</term><term>HIV Infections (drug therapy)</term><term>HIV Infections (virology)</term><term>HIV-1 (drug effects)</term><term>Humans</term><term>Molecular Dynamics Simulation</term><term>Phenylalanine (analogs & derivatives)</term><term>Phenylalanine (chemical synthesis)</term><term>Phenylalanine (pharmacology)</term><term>Small Molecule Libraries (chemical synthesis)</term><term>Small Molecule Libraries (chemistry)</term><term>Small Molecule Libraries (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term><term>Agents antiVIH (pharmacologie)</term><term>Agents antiVIH (synthèse chimique)</term><term>Bibliothèques de petites molécules ()</term><term>Bibliothèques de petites molécules (pharmacologie)</term><term>Bibliothèques de petites molécules (synthèse chimique)</term><term>Capside ()</term><term>Chimie click</term><term>Humains</term><term>Infections à VIH (traitement médicamenteux)</term><term>Infections à VIH (virologie)</term><term>Phénylalanine (analogues et dérivés)</term><term>Phénylalanine (pharmacologie)</term><term>Phénylalanine (synthèse chimique)</term><term>Simulation de dynamique moléculaire</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Phenylalanine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-HIV Agents</term><term>Phenylalanine</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term><term>Phenylalanine</term><term>Small Molecule Libraries</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Phénylalanine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Capsid</term><term>HIV-1</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>HIV Infections</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term><term>Bibliothèques de petites molécules</term><term>Phénylalanine</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Agents antiVIH</term><term>Bibliothèques de petites molécules</term><term>Phénylalanine</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à VIH</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à VIH</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>HIV Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Click Chemistry</term><term>Humans</term><term>Molecular Dynamics Simulation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term><term>Bibliothèques de petites molécules</term><term>Capside</term><term>Chimie click</term><term>Humains</term><term>Simulation de dynamique moléculaire</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of HIV-1 replication and is considered an important, clinically unexploited therapeutic target. As such, small drug-like molecules that inhibit this critical HIV-1 protein have become a priority for several groups. Therefore, in this study we explore small molecule targeting of the CA protein, and in particular a very attractive inter-protomer pocket. We report the design, parallel synthesis, and anti-HIV-1 activity evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors synthesized via Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. We demonstrate robust inhibitory activity over a range of potencies against the HIV-1 NL<sub>4-3</sub> reference strain. In particular, compound 13m exhibited the greatest potency and lowest toxicity within this new series with an EC<sub>50</sub> value of 4.33 μM and CC<sub>50</sub> value of >57.74 μM (SI > 13.33). These values are very similar to the lead compound PF-74 (EC<sub>50</sub> = 5.95 μM, CC<sub>50</sub> > 70.50 μM, SI > 11.85) in our assay, despite significant structural difference. Furthermore, we demonstrate via surface plasmon resonance (SPR) binding assays that 13m interacts robustly with recombinant HIV-1 CA and exhibits antiviral activity in both the early and late stages of HIV-1 replication. Overall, the novel parallel synthesis and structure-activity relationships (SARs) identified within this study set the foundation for further rational optimization and discovery of CA-targeting compounds with improved potency.</div></front></TEI><affiliations><list><country><li>Jordanie</li><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Pennsylvanie</li></region></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Wu, Gaochan" sort="Wu, Gaochan" uniqKey="Wu G" first="Gaochan" last="Wu">Gaochan Wu</name></noRegion><name sortKey="Jing, Lanlan" sort="Jing, Lanlan" uniqKey="Jing L" first="Lanlan" last="Jing">Lanlan Jing</name><name sortKey="Kang, Dongwei" sort="Kang, Dongwei" uniqKey="Kang D" first="Dongwei" last="Kang">Dongwei Kang</name><name sortKey="Liu, Xinyong" sort="Liu, Xinyong" uniqKey="Liu X" first="Xinyong" last="Liu">Xinyong Liu</name><name sortKey="Tian, Ye" sort="Tian, Ye" uniqKey="Tian Y" first="Ye" last="Tian">Ye Tian</name><name sortKey="Zhan, Peng" sort="Zhan, Peng" uniqKey="Zhan P" first="Peng" last="Zhan">Peng Zhan</name><name sortKey="Zhang, Fangfang" sort="Zhang, Fangfang" uniqKey="Zhang F" first="Fangfang" last="Zhang">Fangfang Zhang</name></country><country name="Jordanie"><noRegion><name sortKey="Zalloum, Waleed A" sort="Zalloum, Waleed A" uniqKey="Zalloum W" first="Waleed A" last="Zalloum">Waleed A. Zalloum</name></noRegion></country><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Meuser, Megan E" sort="Meuser, Megan E" uniqKey="Meuser M" first="Megan E" last="Meuser">Megan E. Meuser</name></region><name sortKey="Chen, Chin Ho" sort="Chen, Chin Ho" uniqKey="Chen C" first="Chin-Ho" last="Chen">Chin-Ho Chen</name><name sortKey="Cocklin, Simon" sort="Cocklin, Simon" uniqKey="Cocklin S" first="Simon" last="Cocklin">Simon Cocklin</name><name sortKey="Lee, Kuo Hsiung" sort="Lee, Kuo Hsiung" uniqKey="Lee K" first="Kuo-Hsiung" last="Lee">Kuo-Hsiung Lee</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Ncbi/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002F68 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Checkpoint/biblio.hfd -nk 002F68 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Ncbi
|étape= Checkpoint
|type= RBID
|clé= pubmed:30243152
|texte= Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Ncbi/Checkpoint/RBID.i -Sk "pubmed:30243152" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Checkpoint/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |