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
NeuroVive Pharmaceutical AB, Medicon Village, SE-22381 Lund, Sweden; Mitochondrial Medicine, Lund University, SE-22184 Lund, Sweden.
Isomerase Therapeutics Ltd., Suite 9, Science Village, Chesterford Research Park, Cambridge CB10 1XL, UK; Biotica Technology Ltd., Cambridge CB10 1XL, UK.
Chem Biol. 2015 Feb 19;22(2):285-92. doi: 10.1016/j.chembiol.2014.10.023. Epub 2015 Jan 22.
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.
抑制宿主编码的靶点，如亲环蛋白，为开发强效、高耐药屏障的抗病毒药物以治疗多种病毒性疾病提供了契机。然而，许多靶向宿主的药物是天然产物，仅靠合成化学很难对其进行优化。我们描述了生物工程与半合成化学的正交组合，以优化具有混合非核糖体肽/聚酮来源的已知亲环蛋白抑制剂 sanglifehrin A 的类药性质，从而生成候选药物 NVP018（原 BC556）。NVP018 是乙型肝炎病毒、丙型肝炎病毒（HCV）和 HIV-1 复制的强效抑制剂，对主要药物转运体的抑制作用极小，并且对 HCV 和 HIV-1 耐药性的产生具有高屏障。
