Department of Molecular Discovery Technologies, Bristol-Myers Squibb, Waltham, Massachusetts, USA
Department of Virology, Bristol-Myers Squibb, Wallingford, Connecticut, USA.
Antimicrob Agents Chemother. 2017 Jul 25;61(8). doi: 10.1128/AAC.00508-17. Print 2017 Aug.
A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using selection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity. Resistance profiling studies showed that this inhibitor required 30 passages (151 days) in culture to acquire sufficient resistance to result in viral titer breakthrough. Resistance mapped to the loss of multiple potential N-linked glycosylation sites in gp120, suggesting that inhibition is due to steric hindrance of CD4-binding-induced conformational changes.
一种新型基于纤连蛋白的蛋白质（Adnectin）HIV-1 抑制剂是通过筛选产生的。该抑制剂与人 CD4 具有高亲和力（3.9 nM），并在 CD4 结合后和膜融合前的步骤抑制病毒进入。这种新型抑制剂的前体序列是使用 mRNA 展示从数万亿个 Adnectin 变体库中选择的，然后进一步优化以提高抗病毒和物理性质。最终优化的抑制剂对涵盖 11 个亚型的 124 种包膜 (gp160) 蛋白的面板表现出完全的效力，表明具有广谱活性。耐药性分析研究表明，该抑制剂需要在培养中进行 30 次传代（151 天）才能获得足够的耐药性，从而导致病毒滴度突破。耐药性与 gp120 中多个潜在 N-连接糖基化位点的丢失有关，表明抑制作用是由于 CD4 结合诱导的构象变化的空间位阻。
