HIV-1蛋白酶抑制剂分子设计策略研究进展

由于HIV的强变异性，根据HIV蛋白酶的理化性质、晶体结构及底物的特征，设计、合成、筛选新型高效的蛋白酶抑制剂，一直以来是抗艾滋病药物的热点之一。笔者将近年来研究的HIV蛋白酶抑制剂，接其化学结构分为拟肽和非肽两类，详细介绍了各类HIV蛋白酶抑制剂的分子设计策略、作用机制和活性等方面的研究进展。     

HIV-1蛋白酶抑制剂前药的研究进展

综述HIV1蛋白酶抑制剂前药的研究进展。HIV1蛋白酶抑制剂前药是以HIV1蛋白酶抑制剂为母体,通过引入亲脂性或亲水性基团等结构修饰而得到的一类药物前体,尤其是基于蛋白酶抑制剂和逆转录酶抑制剂为母体药物设计的“双药”型抗HIV1前药,它们能在体内水解释放出母体药物,从而提高母体药物活性及生物利用度,降低其耐药性或交叉耐药性。     

小分子肾素抑制剂研制的近期临床目标

肾素-血管紧张素系统(RAS)的第一步及限速的蛋白水解反应,是血管紧张素原的N末端在肾素的酶促作用下水解为血管紧张素I(AI).对该步的抑制有高度特异性,而对血管紧张素转换酶(ACE)的抑制为非特异性.长期以来,肾素的高特异性吸引了众多药理学家及药物化学家,但也为设计可作药用的肾素抑制剂带来不少问题.例如,ACE的底物可小至酰化的三肽,而肾素的已知最小底物是八肽(化合物1,见表1).因此,似乎肾素抑制剂也必须较大,这就产生了代谢、生物利用度及作用时间方面的问题.故至今口服生物利用度高,     

多肽模拟物的设计

非肽激素，如甾类化合物和儿茶酚胺，已被开发成系列药物。尽管大多数激素为多肽化合物，但由于它们缺乏口服生物利用度，以及体内酶的降解而导致作用时间短，使它们的临床应用受到限制，近年来，小分子库的快速筛选法和合理设计方法已在寻找新型多肽模拟物方面取得一些成功。本文以血管紧张素２为例，对多肽模拟物的合理设计方法进行探讨。     

HIV-1蛋白酶解聚型抑制剂的计算机辅助分子设计

目的：探索性研究和设计HIV-1蛋白酶新型抑制剂—解聚型抑制剂。方法：计算机辅助药物设计的分子对接方法。结果：设计的一系列拟肽分子既可阻挠HIV-1 PR二聚体的组装,又可抑制酶的活性。其中,PP30可作为候选先导物。结论：解聚型抑制剂有望抑制突变的HIV-1 PR。     

基于分子对接和分子动力学模拟技术筛选SARS-CoV-23CL蛋白酶抑制剂

目的 以分子对接和分子动力学模拟技术相结合的方法筛选得到严重急性呼吸系统综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2,SARS-CoV-2) 3CL蛋白酶的小分子抑制剂。方法 基于SARS-CoV-2 3CL蛋白酶的晶体结构(PDB ID:7K3T和7SI9),从PubChem数据库中筛选得到SARS-CoV-2 3CL蛋白酶的特异性抑制剂nirmatrelvir的结构类似物，使用Autodock进行非共价分子对接，使用AutoDockFR进行共价分子对接，采用Pymol和Ligplot软件对SARS-CoV-2 3CL蛋白酶和小分子进行相互作用模式分析，最后使用AMBER18进行小分子化合物与SARS-CoV-2 3CL蛋白酶复合物的分子动力学模拟，进一步验证分子对接结果，使用SwissADME对化合物进行成药性分析。结果 将78个nirmatrelvir结构类似物与SARS-CoV-2 3CL蛋白酶进行虚拟筛选和分子对接，得到了2个与nirmatrelvir作用相当的小分子化合物(PubChem ID:57842...     

新的抗癌药物作用靶点甲硫氨酰氨肽酶-2

夫马洁林是目前已知的最有潜力的天然血管生成抑制剂之一，该类药物通过共价抑制甲硫氨酰氨肽酶－2的活性，而特异性地抑制血管内皮细胞的生长和增殖，根据甲硫氨酰氨肽酶－2的结构以及催化和抑制机制，可以设计和合成新型的血管生成抑制剂；通过最新发展的活性检测方法，可以建立高通量药物筛选模型，以期找到新一代高选择性，高亲和性，高生物利用度的甲硫氨酰肽酶－2的小分子抑制剂，用于抗癌新药的开发。     

多肽类似物—类肽和假肽的研究进展

多肽合成类似物－类肽和假肽是对生物多肽进行结构修饰，以便增强对酶稳定性，提高生物利用度及生物活性，延长作用时间。本文主要综述近年来类肽和假肽在蛋白酶抑制剂和某些天然生物多肽的激动剂／拮抗剂方面的研究进展。     

一种免受胰蛋白酶降解的药物释放系统的开发和体外评价

口服肽类和蛋白质类药物由于顺从性好、易得和经济而倍受病人、临床医生和制药商的欢迎。但多种屏障包括酶、扩散和吸收屏障使此类制剂制造非常困难。开发此类治疗药物口服释药系统以获得足够的生物利用度是今后制药技术迫切需要解决的问题之一。由于胰蛋白酶是肠道最丰富的蛋白酶之一,因此开发治疗性肽类或蛋白质类药物免受胰蛋白酶降解的控释给药系统是目前研究的目标。本研究以胰岛素为模型药物探讨了这种释药系统。材料与方法　(1)聚氨基葡糖-抗痛素(特异性胰蛋白酶抑制剂)结合物的合成:取聚氨基葡糖1g混于90mL软化水中,连续加1mol·L-…     

加贝酯预防治疗性ERCP术后高淀粉酶血症及胰腺炎的研究

内镜逆行胰胆管造影（ERCP）术后胰腺炎及高淀粉酶血症是常见的并发症。而治疗性ERCP由于操作多,操作时间长,应用器械多,故并发症也多,其并发症也重于诊断性ERCP。加贝酯为小分子非肽类蛋白酶抑制剂,临床上治疗急性胰腺炎取得了很好的疗效,现就郑州大学第一附属医院治疗性ERCP168例病例资料分析报告如下：     

Dimeric 4-Aryl-1,4-dihydropyridines: development of a third class of nonpeptidic HIV-1 protease inhibitors

Cross-resistance development against most peptidic HIV-1 protease inhibitors (PI) forces the development of nonpeptidic alternatives. The classes of nonpeptidic protease inhibitors was limited so far to cyclic ureas and 4-hydroxy-2-pyrones with problems of limited bioavailability by extensive metabolism and protein binding. Cage dimeric 4-aryl-1,4-dihydropyridines have been developed as third class of nonpeptidic PIs. In the following synthesis, molecular modeling and biological activities of a first series of the novel PIs are reviewed. Bioavailability of the dimers will not be limited by protein binding and metabolism as far as evaluated.     

Oral absorption of the HIV protease inhibitors: a current update

Although the human immunodeficiency virus (HIV) protease inhibitors are highly effective, they are characterized by low and/or variable bioavailability with limited penetration into the central nervous system (CNS). Their clinical use is limited by patient compliance and by drug-drug interactions. The effect of drug solubility on their oral absorption has been investigated but further evaluation of this relationship is required. First pass metabolism appears to be significant for the HIV protease inhibitors and they are extensively metabolized by cytochrome P450 (CYP) 3A4. Recent studies suggest that these drugs are substrates for the P-glycoprotein efflux pump, which can limit their intestinal absorption and their transport across the blood-brain barrier. Drugs inducing or inhibiting CYP3A4 and/or P-glycoprotein may influence the bioavailability of the HIV protease inhibitors. The low bioavailability, variable absorption and drug-drug interactions of the HIV protease inhibitors may be related to the variability of cytochrome P450 and P-glycoprotein expression and to possible CYP3A4/P-glycoprotein interactions. To improve oral HIV protease inhibitor therapy, it is essential to mechanistically characterize the cell specific, tissue specific and regional intestinal dependencies of drug transport, secretory transport, metabolism and P-glycoprotein/CPY3A4 interactions. This report reviews the physicochemical characteristics and pharmacokinetics of the HIV protease inhibitors while considering the relationships between their hepatic and intestinal metabolism, low bioavailability, variable absorption and drug-drug interactions.     

Progress in the discovery of orally bioavailable inhibitors of HIV protease

Summary The development of inhibitors of HIV protease for the chemotherapy of AIDS has been hampered by the poor pharmacokinetic profile of most inhibitors due to their peptidomimetic nature. Recently, substantial progress in the identification of agents with improved properties has been realized. This Perspective contrasts the preclinical pharmacokinetic parameters of a variety of HIV protease inhibitors with significant oral bioavailability. Inhibitors with high oral C_max/in vitro EC₅₀ ratios have shown substantial suppression of HIV in vivo. The relationship between the structural and physicochemical features and the pharmacokinetic behavior of peptidomimetic inhibitors is discussed.     

Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance

HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.     

Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multidrug resistant HIV-1 strains

Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (K(i) = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC(50) = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P(1)-P(2) position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (K(i) = 0.38 nM, IC(50) = 160 nM).     

New active HIV-1 protease inhibitors derived from 3-hexanol: conformation study of the free inhibitors in crystalline state and in complex with the enzyme

Four novel linear non‐peptidic HIV‐1 protease inhibitors derived from 2,5‐diamino‐1,6‐diphenyl‐3‐hexanol were synthesized and characterized. All of them exhibit tight binding to HIV‐1 protease, with inhibition constants K_i in the range 20 pm –5 nm . The investigated inhibitors were crystallized, and their crystal structures were determined by X‐ray diffraction. In all cases, the conformations found in the crystalline state differ significantly from the conformations obtained by computational docking of the inhibitor in the binding cleft of native HIV‐1 protease. Owing to the prevalence of hydrophobic substituents in all these inhibitors, the conformational mobility in water solution is restricted to their compact forms. The spectrum of low‐energy conformations in solution dramatically changes during the formation of inhibitor crystals (phenyl ring stacking as a leading motif) or during the formation of a complex with HIV‐1 protease (elongated conformation suitable to fit the enzyme pockets as a factor responsible for tight binding). High conformational flexibility and low conformational stress in the molecules of these inhibitors most likely increase their biological activity in comparison with more rigid compounds.     

HIV protease: Structure-based design

Summary Close examination of the X-ray crystallographic structures of complexes of prototypical HIV protease inhibitors drawn from diverse structural classes and bound to either synthetic or recombinant HIV protease reveals a remarkable degree of conservation vis-à-vis the protein's homodimeric backbone geometry and key features of its inhibitor binding site. Subtle concerted movements of the amino acid side chains lining this cavity and making contact with inhibitors are evident in exquisite detail in the most highly resolved structures. They are responsible for the enzyme's selectivity. As noted in the preceding perspective on X-ray crystallographic studies, HIV protease is rapidly becoming one of the most well-studied proteins.As a modeler one is encouraged to use the available structural data to predict the binding modes of other classes of HIV protease inhibitors for which X-ray data are unavailable and also as templates to guide the design of further novel inhibitors, which hopefully have some advantages over existing structures. The improvements sought typically involve structural simplification, metabolic stability, or most of all, increased in vivo potency and oral bioavailability. While the structural outcome may or may not bear resemblance to any one of the original reference inhibitor structures, we refer to this process as one ofstructure-based design to emphasize its dependence on critical analyses of the properties and behavior of these experimental datasets.Computational methodologies are available to analyze and compare these datasets in some depth, and to display and manipulate them interactively, in various complementary visualization formats, as a preliminary to undertaking any structurally directed synthetic initiatives. Likewise, efficient molecular-mechanics software tools are on hand to explore the conformational changes around the active site, which are needed to build in or to dock models of new inhibitor structures; either prospectively, for evaluation as potential synthetic targets, or retrospectively, to help rationalize the SAR of a known series or lead in the context of a more realistic active site-bound model.To date these design techniques and strategies have been applied mainly to the optimization of established peptidomimetic leads and to rationalize the binding modes of new peptidomimetic inhibitor classes. However, examples exist of applications to the binding modes of nonpeptidic inhibitors and of limited attempts at de novo structure-based design.