Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection

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 synth...

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Bibliographic Details
Published in:Chemistry & biology 2015-02, Vol.22 (2), p.285-292
Main Authors: Hansson, Magnus Joakim, Moss, Steven James, Bobardt, Michael, Chatterji, Udayan, Coates, Nigel, Garcia-Rivera, Jose A., Elmér, Eskil, Kendrew, Steve, Leyssen, Pieter, Neyts, Johan, Nur-E-Alam, Mohammad, Warneck, Tony, Wilkinson, Barrie, Gallay, Philippe, Gregory, Matthew Alan
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Antiviral Agents - therapeutic use
Bioengineering
Cardiac and Cardiovascular Systems
Clinical Medicine
Cyclophilins - antagonists & inhibitors
Cyclophilins - metabolism
Disease Models, Animal
Dogs
Half-Life
Hep G2 Cells
Hepacivirus - enzymology
Hepacivirus - physiology
Hepatitis B virus - physiology
HIV Infections - prevention & control
HIV-1 - physiology
Humans
Kardiologi
Klinisk medicin
Lactones - chemistry
Lactones - metabolism
Lactones - pharmacology
Lungmedicin och allergi
Medical and Health Sciences
Medicin och hälsovetenskap
Mice
Mice, SCID
Neurologi
Neurology
Oxazines - chemistry
Oxazines - metabolism
Oxazines - pharmacology
Rats
Respiratory Medicine and Allergy
Streptomyces - chemistry
Streptomyces - metabolism
Virus Replication - drug effects
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Summary: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. •Optimization and preclinical analysis of a bacterial natural product•Combination of bioengineering and semisynthetic chemistry•Preclinical analysis revealing potent antiviral activity Hansson et al. describe the generation and preclinical analysis of a bacterial natural product with activity as a host-targeted antiviral drug. This was generated by a combination of biosynthetic engineering and semisynthetic chemistry.
ISSN:1074-5521
1879-1301
1879-1301
DOI:10.1016/j.chembiol.2014.10.023