标题： HIV-1-PR抑制剂的设计，不会产生耐药性：阻止单体的折叠 显示英文标题

标题： Design of HIV-1-PR inhibitors which do not create resistance: blocking the folding of single monomers

摘要： 药物设计的主要问题之一是优化药物与靶点的相互作用。 在靶点是一种表现出高突变率的病毒蛋白的情况下，会出现第二个问题，即最终产生耐药性。 我们希望提出一种非传统药物的设计方案，这些药物不会面临这些问题，并将其应用于HIV-1蛋白酶的情况。 该方案基于这样的知识：单结构域蛋白质的折叠，例如构成HIV-1-PR同源二聚体的每个单体，是由局部基本结构（LES）控制的，这些结构由疏水性、强烈相互作用且高度保守的氨基酸之间的局部接触所稳定，在折叠过程中起着核心作用。 由于LES经过数百万代的进化，能够识别并强烈相互作用，以使蛋白质快速折叠并避免与其他蛋白质聚集，因此高度特异性（因此毒性较低）且有效的折叠抑制剂药物自然显现出来：显示LES相同氨基酸序列的短肽（或最终其模拟分子），即p-LES。 除了具有特异性和高效性外，这些抑制剂预计不会引起耐药性：事实上，成功避开它们作用的突变会导致一个或多个LES的不稳定，从而导致蛋白质变性。 利用简单但不过于简化的模型框架中的蒙特卡洛模拟，该模型能够再现单体蛋白的主要热力学和动态特性，我们首先确定HIV-1-PR的LES，然后表明相应的p-LES肽作为有效抑制蛋白酶折叠的物质，不会产生耐药性。 显示英文摘要

摘要： One of the main problems of drug design is that of optimizing the drug--target interaction. In the case in which the target is a viral protein displaying a high mutation rate, a second problem arises, namely the eventual development of resistance. We wish to suggest a scheme for the design of non--conventional drugs which do not face any of these problems and apply it to the case of HIV--1 protease. It is based on the knowledge that the folding of single--domain proteins, like e.g. each of the monomers forming the HIV--1--PR homodimer, is controlled by local elementary structures (LES), stabilized by local contacts among hydrophobic, strongly interacting and highly conserved amino acids which play a central role in the folding process. Because LES have evolved over myriads of generations to recognize and strongly interact with each other so as to make the protein fold fast as well as to avoid aggregation with other proteins, highly specific (and thus little toxic) as well as effective folding--inhibitor drugs suggest themselves: short peptides (or eventually their mimetic molecules), displaying the same amino acid sequence of that of LES (p--LES). Aside from being specific and efficient, these inhibitors are expected not to induce resistance: in fact, mutations which successfully avoid their action imply the destabilization of one or more LES and thus should lead to protein denaturation. Making use of Monte Carlo simulations within the framework of a simple although not oversimplified model, which is able to reproduce the main thermodynamic as well as dynamic properties of monoglobular proteins, we first identify the LES of the HIV--1--PR and then show that the corresponding p--LES peptides act as effective inhibitors of the folding of the protease which do not create resistance.