HIV-1 Protease Inhibitors from Inverse Design in the Substrate Envelope Exhibit Subnanomolar Binding to Drug-Resistant Variants

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• 作者：Michael D. Altman ; Akbar Ali ; G. S. Kiran Kumar Reddy ; Madhavi N. L. Nalam ; Saima Ghafoor Anjum ; Hong Cao ; Sripriya Chellappan ; Visvaldas Kairys ; Miguel X. Fernandes ; Michael K. Gilson ; Celia A. Schif
• 刊名：Journal of the American Chemical Society
• 出版年：2008
• 出版时间：May 14, 2008
• 年：2008
• 卷：130
• 期：19
• 页码：6099 - 6113
• 全文大小：905K
• 年卷期：v.130,no.19(May 14, 2008)
• ISSN：1520-5126

文摘

The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a K_i of 30–50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6–13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14–16-fold), moderate binders (35–80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.