Nalam Madhavi N L, Ali Akbar, Reddy G S Kiran Kumar, Cao Hong, Anjum Saima G, Altman Michael D, Yilmaz Nese Kurt, Tidor Bruce, Rana Tariq M, Schiffer Celia A
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Chem Biol. 2013 Sep 19;20(9):1116-24. doi: 10.1016/j.chembiol.2013.07.014. Epub 2013 Sep 5.
The rapid evolution of HIV under selective drug pressure has led to multidrug resistant (MDR) strains that evade standard therapies. We designed highly potent HIV-1 protease inhibitors (PIs) using the substrate envelope model, which confines inhibitors within the consensus volume of natural substrates, providing inhibitors less susceptible to resistance because a mutation affecting such inhibitors will simultaneously affect viral substrate processing. The designed PIs share a common chemical scaffold but utilize various moieties that optimally fill the substrate envelope, as confirmed by crystal structures. The designed PIs retain robust binding to MDR protease variants and display exceptional antiviral potencies against different clades of HIV as well as a panel of 12 drug-resistant viral strains. The substrate envelope model proves to be a powerful strategy to develop potent and robust inhibitors that avoid drug resistance.
在选择性药物压力下,HIV的快速进化导致了能逃避标准疗法的多药耐药(MDR)毒株。我们利用底物包封模型设计了高效的HIV-1蛋白酶抑制剂(PIs),该模型将抑制剂限制在天然底物的共有体积内,使抑制剂不易产生耐药性,因为影响此类抑制剂的突变会同时影响病毒底物的加工。经晶体结构证实,设计出的PIs具有共同的化学骨架,但利用了各种能最佳填充底物包封的基团。设计出的PIs与MDR蛋白酶变体保持着强大的结合力,对HIV的不同分支以及一组12种耐药病毒株均表现出卓越的抗病毒效力。底物包封模型被证明是开发强效且不易产生耐药性的抑制剂的有力策略。