Abstract |
Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/ polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.
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Authors | Magnus Joakim Hansson, Steven James Moss, Michael Bobardt, Udayan Chatterji, Nigel Coates, Jose A Garcia-Rivera, Eskil Elmér, Steve Kendrew, Pieter Leyssen, Johan Neyts, Mohammad Nur-E-Alam, Tony Warneck, Barrie Wilkinson, Philippe Gallay, Matthew Alan Gregory |
Journal | Chemistry & biology
(Chem Biol)
Vol. 22
Issue 2
Pg. 285-92
(Feb 19 2015)
ISSN: 1879-1301 [Electronic] United States |
PMID | 25619934
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2015 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antiviral Agents
- Lactones
- NVP018
- Oxazines
- Cyclophilins
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Topics |
- Animals
- Antiviral Agents
(chemistry, pharmacology, therapeutic use)
- Bioengineering
- Cyclophilins
(antagonists & inhibitors, metabolism)
- Disease Models, Animal
- Dogs
- HIV Infections
(prevention & control)
- HIV-1
(physiology)
- Half-Life
- Hep G2 Cells
- Hepacivirus
(enzymology, physiology)
- Hepatitis B virus
(physiology)
- Humans
- Lactones
(chemistry, metabolism, pharmacology)
- Mice
- Mice, SCID
- Oxazines
(chemistry, metabolism, pharmacology)
- Rats
- Streptomyces
(chemistry, metabolism)
- Virus Replication
(drug effects)
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