Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity.
Identifieur interne : 001336 ( Main/Exploration ); précédent : 001335; suivant : 001337Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity.
Auteurs : Hannah L. Peters [États-Unis] ; Dirk Jochmans [Belgique] ; Adriaan H. De Wilde [Pays-Bas] ; Clara C. Posthuma [Pays-Bas] ; Eric J. Snijder [Pays-Bas] ; Johan Neyts [Belgique] ; Katherine L. Seley-Radtke [États-Unis]Source :
- Bioorganic & medicinal chemistry letters [ 1464-3405 ] ; 2015.
Descripteurs français
- KwdFr :
- Aciclovir (analogues et dérivés), Aciclovir (pharmacologie), Animaux, Antiviraux (), Antiviraux (pharmacologie), Cellules Vero, Conception de médicament, Coronavirus (), Coronavirus (physiologie), Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie), Coronavirus humain NL63 (), Coronavirus humain NL63 (physiologie), Humains, Infections à coronavirus (traitement médicamenteux), Nucléosides (), Nucléosides (pharmacologie), Réplication virale (), Virus du SRAS (), Virus du SRAS (physiologie).
- MESH :
- analogues et dérivés : Aciclovir.
- pharmacologie : Aciclovir, Antiviraux, Nucléosides.
- physiologie : Coronavirus, Coronavirus du syndrome respiratoire du Moyen-Orient, Coronavirus humain NL63, Virus du SRAS.
- traitement médicamenteux : Infections à coronavirus.
- Animaux, Antiviraux, Cellules Vero, Conception de médicament, Coronavirus, Coronavirus du syndrome respiratoire du Moyen-Orient, Coronavirus humain NL63, Humains, Nucléosides, Réplication virale, Virus du SRAS.
English descriptors
- KwdEn :
- Acyclovir (analogs & derivatives), Acyclovir (pharmacology), Animals, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Chlorocebus aethiops, Coronavirus (drug effects), Coronavirus (physiology), Coronavirus Infections (drug therapy), Coronavirus NL63, Human (drug effects), Coronavirus NL63, Human (physiology), Drug Design, Humans, Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (physiology), Nucleosides (chemistry), Nucleosides (pharmacology), SARS Virus (drug effects), SARS Virus (physiology), Vero Cells, Virus Replication (drug effects).
- MESH :
- chemical , analogs & derivatives : Acyclovir.
- chemical , chemistry : Antiviral Agents, Nucleosides.
- chemical , pharmacology : Acyclovir, Antiviral Agents, Nucleosides.
- drug effects : Coronavirus, Coronavirus NL63, Human, Middle East Respiratory Syndrome Coronavirus, SARS Virus, Virus Replication.
- drug therapy : Coronavirus Infections.
- physiology : Coronavirus, Coronavirus NL63, Human, Middle East Respiratory Syndrome Coronavirus, SARS Virus.
- Animals, Chlorocebus aethiops, Drug Design, Humans, Vero Cells.
Abstract
A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 μM and a CC50 >100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.
DOI: 10.1016/j.bmcl.2015.05.039
PubMed: 26048809
Affiliations:
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Peters</name><affiliation wicri:level="4"><nlm:affiliation>University of Maryland, Baltimore County, Department of Chemistry & Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Maryland, Baltimore County, Department of Chemistry & Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250</wicri:regionArea><placeName><region type="state">Maryland</region><settlement type="city">College Park (Maryland)</settlement></placeName><orgName type="university">Université du Maryland</orgName></affiliation></author><author><name sortKey="Jochmans, Dirk" sort="Jochmans, Dirk" uniqKey="Jochmans D" first="Dirk" last="Jochmans">Dirk Jochmans</name><affiliation wicri:level="1"><nlm:affiliation>Rega Institute, University of Leuven (KULeuven), Minderbroederstraat 10, Leuven BE-3000, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Rega Institute, University of Leuven (KULeuven), Minderbroederstraat 10, Leuven BE-3000</wicri:regionArea><wicri:noRegion>Leuven BE-3000</wicri:noRegion></affiliation></author><author><name sortKey="De Wilde, Adriaan H" sort="De Wilde, Adriaan H" uniqKey="De Wilde A" first="Adriaan H" last="De Wilde">Adriaan H. De Wilde</name><affiliation wicri:level="1"><nlm:affiliation>Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden</wicri:regionArea><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Posthuma, Clara C" sort="Posthuma, Clara C" uniqKey="Posthuma C" first="Clara C" last="Posthuma">Clara C. Posthuma</name><affiliation wicri:level="1"><nlm:affiliation>Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden</wicri:regionArea><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><affiliation wicri:level="1"><nlm:affiliation>Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden</wicri:regionArea><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Neyts, Johan" sort="Neyts, Johan" uniqKey="Neyts J" first="Johan" last="Neyts">Johan Neyts</name><affiliation wicri:level="1"><nlm:affiliation>Rega Institute, University of Leuven (KULeuven), Minderbroederstraat 10, Leuven BE-3000, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Rega Institute, University of Leuven (KULeuven), Minderbroederstraat 10, Leuven BE-3000</wicri:regionArea><wicri:noRegion>Leuven BE-3000</wicri:noRegion></affiliation></author><author><name sortKey="Seley Radtke, Katherine L" sort="Seley Radtke, Katherine L" uniqKey="Seley Radtke K" first="Katherine L" last="Seley-Radtke">Katherine L. Seley-Radtke</name><affiliation wicri:level="4"><nlm:affiliation>University of Maryland, Baltimore County, Department of Chemistry & Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250, USA. Electronic address: kseley@umbc.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>University of Maryland, Baltimore County, Department of Chemistry & Biochemistry, 1000 Hilltop Circle, Baltimore, MD 21250</wicri:regionArea><placeName><region type="state">Maryland</region><settlement type="city">College Park (Maryland)</settlement></placeName><orgName type="university">Université du Maryland</orgName></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry letters</title><idno type="eISSN">1464-3405</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acyclovir (analogs & derivatives)</term><term>Acyclovir (pharmacology)</term><term>Animals</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Chlorocebus aethiops</term><term>Coronavirus (drug effects)</term><term>Coronavirus (physiology)</term><term>Coronavirus Infections (drug therapy)</term><term>Coronavirus NL63, Human (drug effects)</term><term>Coronavirus NL63, Human (physiology)</term><term>Drug Design</term><term>Humans</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Middle East Respiratory Syndrome Coronavirus (physiology)</term><term>Nucleosides (chemistry)</term><term>Nucleosides (pharmacology)</term><term>SARS Virus (drug effects)</term><term>SARS Virus (physiology)</term><term>Vero Cells</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Aciclovir (analogues et dérivés)</term><term>Aciclovir (pharmacologie)</term><term>Animaux</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Cellules Vero</term><term>Conception de médicament</term><term>Coronavirus ()</term><term>Coronavirus (physiologie)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (physiologie)</term><term>Coronavirus humain NL63 ()</term><term>Coronavirus humain NL63 (physiologie)</term><term>Humains</term><term>Infections à coronavirus (traitement médicamenteux)</term><term>Nucléosides ()</term><term>Nucléosides (pharmacologie)</term><term>Réplication virale ()</term><term>Virus du SRAS ()</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Acyclovir</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Nucleosides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Acyclovir</term><term>Antiviral Agents</term><term>Nucleosides</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Aciclovir</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term><term>Coronavirus NL63, Human</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>SARS Virus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Aciclovir</term><term>Antiviraux</term><term>Nucléosides</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Coronavirus humain NL63</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Coronavirus</term><term>Coronavirus NL63, Human</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Chlorocebus aethiops</term><term>Drug Design</term><term>Humans</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Antiviraux</term><term>Cellules Vero</term><term>Conception de médicament</term><term>Coronavirus</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Coronavirus humain NL63</term><term>Humains</term><term>Nucléosides</term><term>Réplication virale</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 μM and a CC50 >100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Pays-Bas</li><li>États-Unis</li></country><region><li>Maryland</li></region><settlement><li>College Park (Maryland)</li></settlement><orgName><li>Université du Maryland</li></orgName></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Peters, Hannah L" sort="Peters, Hannah L" uniqKey="Peters H" first="Hannah L" last="Peters">Hannah L. Peters</name></region><name sortKey="Seley Radtke, Katherine L" sort="Seley Radtke, Katherine L" uniqKey="Seley Radtke K" first="Katherine L" last="Seley-Radtke">Katherine L. Seley-Radtke</name></country><country name="Belgique"><noRegion><name sortKey="Jochmans, Dirk" sort="Jochmans, Dirk" uniqKey="Jochmans D" first="Dirk" last="Jochmans">Dirk Jochmans</name></noRegion><name sortKey="Neyts, Johan" sort="Neyts, Johan" uniqKey="Neyts J" first="Johan" last="Neyts">Johan Neyts</name></country><country name="Pays-Bas"><noRegion><name sortKey="De Wilde, Adriaan H" sort="De Wilde, Adriaan H" uniqKey="De Wilde A" first="Adriaan H" last="De Wilde">Adriaan H. De Wilde</name></noRegion><name sortKey="Posthuma, Clara C" sort="Posthuma, Clara C" uniqKey="Posthuma C" first="Clara C" last="Posthuma">Clara C. Posthuma</name><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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