Effects of HIV-1 protease on cellular functions and their potential applications in antiretroviral therapy
Effects of HIV-1 protease on cellular functions and their potential applications in antiretroviral therapy
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HIV-1蛋白酶对细胞功能的影响及其在抗逆转录病毒治疗中的潜在应用
作者：
Hailiu Yang;Joseph Nkeze;R. Y. Zhao
人类免疫缺陷病毒 1 型 (HIV-1) 蛋白酶抑制剂 (PI) 是抗逆转录病毒治疗中最有效的一类药物。然而，病毒对 PI 的耐药性可能会迅速出现，从而降低这些药物的有效性。值得注意的是，目前 FDA 批准的所有 PI 都是竞争性抑制剂，即与底物竞争活性酶位点的抑制剂。这种常见的抑制方法增加了产生对许多或所有现有 PI 具有抗药性的 HIV-1 耐药株的可能性。因此，需要远离活性酶位点当前靶点的新 PI。具体而言，应寻找变构抑制剂，即通过与 PR 非竞争性结合来抑制 PR 酶活性的抑制剂。目前PI的另一个共同特点是它们都是基于基于结构的设计开发的。基于结构的策略衍生的药物可能会产生目标特异性和有效的抑制剂。然而，这种类型的药物设计一次只能靶向一个位点，并且通过这种方法发现的药物通常与细胞毒性等强烈副作用相关，限制了其靶点选择的数量、功效和适用性。相比之下，基于细胞的系统可以提供一种有用的替代策略，可以克服与基于结构的药物设计相关的许多遗传缺点。例如，可以使用基于细胞的系统来寻找变构PI，而无需考虑抑制位点或机制。此外，基于细胞的系统可以消除那些具有强细胞毒性作用的PI。最重要的是，简单、经济且易于维护的真核细胞系统（例如酵母）将使我们能够在大规模高通量筛选（HTS）系统中寻找潜在的PI，从而增加成功的机会。基于我们多年使用裂殖酵母作为研究 HIV-1 Vpr 的模型系统的经验，我们建议使用裂殖酵母作为可能的替代系统来研究 HIV-1 蛋白酶对细胞功能的影响，并探索其作为 HTS 系统的实用性，以寻找新的 PI 来对抗 HIV-1 耐药菌株。
Human Immunodeficiency Virus Type 1 (HIV-1) protease inhibitors (PIs) are the most potent class of drugs in antiretroviral therapies. However, viral drug resistance to PIs could emerge rapidly thus reducing the effectiveness of those drugs. Of note, all current FDA-approved PIs are competitive inhibitors, i.e., inhibitors that compete with substrates for the active enzymatic site. This common inhibitory approach increases the likelihood of developing drug resistant HIV-1 strains that are resistant to many or all current PIs. Hence, new PIs that move away from the current target of the active enzymatic site are needed. Specifically, allosteric inhibitors, inhibitors that prohibit PR enzymatic activities through non-competitive binding to PR, should be sought. Another common feature of current PIs is they were all developed based on the structure-based design. Drugs derived from a structure-based strategy may generate target specific and potent inhibitors. However, this type of drug design can only target one site at a time and drugs discovered by this method are often associated with strong side effects such as cellular toxicity, limiting its number of target choices, efficacy, and applicability. In contrast, a cell-based system may provide a useful alternative strategy that can overcome many of the inherited shortcomings associated with structure-based drug designs. For example, allosteric PIs can be sought using a cell-based system without considering the site or mechanism of inhibition. In addition, a cell-based system can eliminate those PIs that have strong cytotoxic effect. Most importantly, a simple, economical, and easy-to-maintained eukaryotic cellular system such as yeast will allow us to search for potential PIs in a large-scaled high throughput screening (HTS) system, thus increasing the chances of success. Based on our many years of experience in using fission yeast as a model system to study HIV-1 Vpr, we propose the use of fission yeast as a possible surrogate system to study the effects of HIV-1 protease on cellular functions and to explore its utility as a HTS system to search for new PIs to battle HIV-1 resistant strains.
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影响因子：
2.7
作者：
Ghosh, Arun K.;Chapsal, Bruno D.;Steffey, Melinda;Agniswamy, Johnson;Wang, Yuan-Fang;Amano, Masayuki;Weber, Irene T.;Mitsuya, Hiroaki
通讯作者：
Mitsuya, Hiroaki
DOI：
10.1073/pnas.86.3.807
发表时间：
1989-02-01
影响因子：
11.1
作者：
KRAUSSLICH, HG;INGRAHAM, RH;CARTER, CA
通讯作者：
CARTER, CA
影响因子：
4
作者：
B. Höner;R. Shoeman;P. Traub
通讯作者：
B. Höner;R. Shoeman;P. Traub
HIV-1 病毒生命周期中的 Vpr-宿主相互作用。
DOI：
10.1007/s11481-011-9261-z
发表时间：
2011
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
--
作者：
Zhao,RichardY;Li,Ge;Bukrinsky,MichaelI
通讯作者：
Bukrinsky,MichaelI
HIV-1 病毒蛋白 R 与宿主细胞蛋白的相互作用。
DOI：
10.1016/s1054-3589(07)55007-6
发表时间：
2007
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Zhao,RichardY;Elder,RobertT;Bukrinsky,Michael
通讯作者：
Bukrinsky,Michael