title: 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.
authors.affiliation: NeuroVive Pharmaceutical AB, Medicon Village, SE-22381 Lund, Sweden; Mitochondrial Medicine, Lund University, SE-22184 Lund, Sweden.
authors.forename: Magnus Joakim
authors.initials: MJ
authors.lastname: Hansson
authors.affiliation: Isomerase Therapeutics Ltd., Suite 9, Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK; Biotica Technology Ltd., Cambridge CB10 1XL, UK.
authors.forename: Steven James
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bobardt
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Udayan
authors.initials: U
authors.lastname: Chatterji
authors.affiliation: Isomerase Therapeutics Ltd., Suite 9, Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK; Biotica Technology Ltd., Cambridge CB10 1XL, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Coates
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Garcia-Rivera
authors.affiliation: NeuroVive Pharmaceutical AB, Medicon Village, SE-22381 Lund, Sweden; Mitochondrial Medicine, Lund University, SE-22184 Lund, Sweden.
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
authors.affiliation: Biotica Technology Ltd., Cambridge CB10 1XL, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Kendrew
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, K.U. Leuven, 3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, K.U. Leuven, 3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Biotica Technology Ltd., Cambridge CB10 1XL, UK.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Nur-E-Alam
authors.affiliation: Biotica Technology Ltd., Cambridge CB10 1XL, UK.
authors.forename: Tony
authors.initials: T
authors.lastname: Warneck
authors.affiliation: 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.
authors.forename: Barrie
authors.initials: B
authors.lastname: Wilkinson
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: gallay@scripps.edu.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gallay
authors.affiliation: 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.
authors.forename: Matthew Alan
authors.initials: MA
authors.lastname: Gregory
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D057005:Bioengineering; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000502:physiology; D006207:Half-Life; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000201:enzymology / Q000502:physiology; D006515:Hepatitis B virus / Q000502:physiology; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D010078:Oxazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013302:Streptomyces / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007783:Lactones; C000602705:NVP018; D010078:Oxazines; D021983:Cyclophilins