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Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection.

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.
AuthorsMagnus 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
JournalChemistry & biology (Chem Biol) Vol. 22 Issue 2 Pg. 285-92 (Feb 19 2015) ISSN: 1879-1301 [Electronic] United States
PMID25619934 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 Elsevier Ltd. All rights reserved.
Chemical References
  • Antiviral Agents
  • Lactones
  • NVP018
  • Oxazines
  • Cyclophilins
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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