2. Academic Validation
  3. Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection

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

  • Chem Biol. 2015 Feb 19;22(2):285-92. doi: 10.1016/j.chembiol.2014.10.023.
Magnus Joakim Hansson 1,  Steven James Moss 2,  Michael Bobardt 3,  Udayan Chatterji 3,  Nigel Coates 2,  Jose A Garcia-Rivera 3,  Eskil Elmér 1,  Steve Kendrew 4,  Pieter Leyssen 5,  Johan Neyts 5,  Mohammad Nur-E-Alam 4,  Tony Warneck 4,  Barrie Wilkinson 6,  Philippe Gallay 7,  Matthew Alan Gregory 8
Affiliations

Affiliations

  • 1 NeuroVive Pharmaceutical AB, Medicon Village, SE-22381 Lund, Sweden; Mitochondrial Medicine, Lund University, SE-22184 Lund, Sweden.
  • 2 Isomerase Therapeutics Ltd., Suite 9, Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK; Biotica Technology Ltd., Cambridge CB10 1XL, UK.
  • 3 Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 4 Biotica Technology Ltd., Cambridge CB10 1XL, UK.
  • 5 Department of Microbiology and Immunology, Rega Institute for Medical Research, K.U. Leuven, 3000 Leuven, Belgium.
  • 6 Isomerase Therapeutics Ltd., Suite 9, Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK; Biotica Technology Ltd., Cambridge CB10 1XL, UK; Department of Molecular Microbiology, John Innes Centre, Norwich NR4 7UH, UK.
  • 7 Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: gallay@scripps.edu.
  • 8 Isomerase Therapeutics Ltd., Suite 9, Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK; Biotica Technology Ltd., Cambridge CB10 1XL, UK. Electronic address: matt.gregory@isomerase.co.uk.
PMID: 25619934 DOI: 10.1016/j.chembiol.2014.10.023
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.

Figures
Products