Biotica Technology Ltd., Chesterford Research Park, Cambridge CB10 1XL, United Kingdom.
Antimicrob Agents Chemother. 2011 May;55(5):1975-81. doi: 10.1128/AAC.01627-10. Epub 2011 Mar 7.
Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F<4%) and low solubility (<25 μM), although the half-lives (t1/2) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t1/2>5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.
环孢菌素抑制剂目前正在进行丙型肝炎病毒（HCV）的临床试验，都是环孢菌素（CsA）的类似物。桑菲林是一组天然存在的环孢素结合聚酮化合物，其结构与环孢菌素不同，由一种易于进行生物合成工程的微生物产生，可用于先导化合物优化和通过发酵进行大规模生产。对这类化合物用于治疗 HCV 的潜在用途的临床前特征进行了描述，结果表明，天然桑菲林 A 至 D 与 CsA 相比，在破坏 NS5A-CypA、-CypB 和 -CypD 复合物的形成以及抑制 CypA、CypB 和 CypD 异构酶活性方面都更有效。特别是，桑菲林 B（SfB）在抑制所有测试的 Cyp 异构酶活性方面比 CsA 有效 30 至 50 倍，并且也被证明是 1b 亚基因组复制子的更有效的抑制剂（在 Huh 5-2 和 Huh 9-13 细胞中，50%有效浓度[EC50]分别为 0.070 μM 和 0.16 μM）。物理化学和小鼠药代动力学分析表明口服生物利用度低（F<4%），溶解度低（<25 μM），尽管 SfA 和 SfB 在静脉内（i.v.）给药后在小鼠血液中的半衰期（t1/2）较长（t1/2>5 h）。这些数据表明，天然存在的桑菲林是开发新型类似物的合适先导化合物，这些类似物的免疫抑制作用更低，并且具有改善的代谢和药代动力学特性。
