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

Hansson, Magnus LU ; Moss, Steven James; Bobardt, Michael; Chatterji, Udayan; Coates, Nigel; Garcia-Rivera, Jose A; Elmer, Eskil LU ; Kendrew, Steve; Leyssen, Pieter and Neyts, Johan, et al. (2015) In Chemistry and Biology 22(2). p.285-292
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,... (More)
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. (Less)
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Contribution to journal
publication status
published
subject
in
Chemistry and Biology
volume
22
issue
2
pages
285 - 292
publisher
Cell Press
external identifiers
  • pmid:25619934
  • wos:000349966200013
  • scopus:84923142128
ISSN
1879-1301
DOI
10.1016/j.chembiol.2014.10.023
language
English
LU publication?
yes
id
82d7c7ee-c189-431d-8b60-9a15b8502cdd (old id 5039711)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25619934?dopt=Abstract
date added to LUP
2015-02-04 17:20:54
date last changed
2017-02-26 03:08:06
@article{82d7c7ee-c189-431d-8b60-9a15b8502cdd,
  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.},
  author       = {Hansson, Magnus and Moss, Steven James and Bobardt, Michael and Chatterji, Udayan and Coates, Nigel and Garcia-Rivera, Jose A and Elmer, Eskil and Kendrew, Steve and Leyssen, Pieter and Neyts, Johan and Nur-E-Alam, Mohammad and Warneck, Tony and Wilkinson, Barrie and Gallay, Philippe and Gregory, Matthew Alan},
  issn         = {1879-1301},
  language     = {eng},
  number       = {2},
  pages        = {285--292},
  publisher    = {Cell Press},
  series       = {Chemistry and Biology},
  title        = {Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.},
  url          = {http://dx.doi.org/10.1016/j.chembiol.2014.10.023},
  volume       = {22},
  year         = {2015},
}