Development of Dual-Acting Pyrimidinediones as Novel and Highly Potent Topical Anti-HIV Microbicides
Development of Dual-Acting Pyrimidinediones as Novel and Highly Potent Topical Anti-HIV Microbicides
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DOI：
10.1128/aac.05237-11
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发表时间：
2011-11-01
影响因子：
4.9
通讯作者：
Buckheit, Robert W., Jr.
中科院分区：
文献类型：
--
作者：
Buckheit, Karen Watson;Yang, Lu;Buckheit, Robert W., Jr.
在缺乏针对人类免疫缺陷病毒（HIV）的有效疫苗的情况下，预防艾滋病毒性传播的局部杀菌剂是防止感染持续传播的重要策略。新型杀菌剂候选物开发的最新趋势包括使用 FDA 批准的针对 HIV 生命周期早期阶段的治疗药物，包括进入抑制剂和逆转录酶抑制剂。我们研究了 12 种具有有效 HIV 活性的嘧啶二酮化合物及其抑制病毒进入和逆转录的能力，以确定用于产品开发的主要杀菌剂。评估了候选化合物对新鲜人外周血单核细胞中的 B、C 和 E 亚型临床病毒株以及单核巨噬细胞和树突细胞中的 CCR5 嗜性病毒株的功效。还在各种已建立的和新鲜的人类细胞以及针对阴道环境中常见的乳杆菌菌株中进行了杀微生物剂特异性的生物测定和毒性评估。这些评估导致在嘧啶二酮的 N-1 位具有环丙基和环丁基取代基的同系物被鉴定为构效关系系列中最活跃的分子。嘧啶二酮类代表了优异的杀菌剂候选物，因为它们对 HIV-1（亚纳摩尔浓度范围）具有显着高效，效力（治疗指数，> 100 万），溶解度特征以及抗病毒作用的双重机制，其中包括病毒整合之前的病毒复制的两个早期步骤，这被认为对杀菌活性最重要。
In the absence of an effective vaccine against the human immunodeficiency virus (HIV), topical microbicides to prevent the sexual transmission of HIV represent an important strategy to prevent the continued spread of infection. The recent trend in the development of new microbicide candidates includes the utilization of FDA-approved therapeutic drugs that target the early stages of the HIV life cycle, including entry inhibitors and reverse transcriptase inhibitors. We have investigated 12 pyrimidinedione compounds with potent HIV activities and their abilities to inhibit both virus entry and reverse transcription, in an effort to determine a lead microbicide for product development. The candidate compounds were evaluated for efficacy against subtype B, C, and E clinical virus strains in fresh human peripheral blood mononuclear cells and against CCR5-tropic virus strains in both monocyte-macrophages and dendritic cells. Microbicide-specific biological assays and toxicity evaluations were also performed in a variety of established and fresh human cells as well as against Lactobacillus strains common to the vaginal environment. These evaluations resulted in the identification of congeners with cyclopropyl and cyclobutyl substituents at the N-1 of the pyrimidinedione as the most active molecules in the structure-activity relationship series. The pyrimidinediones represent excellent microbicide candidates in light of their significantly high efficacies against HIV-1 (subnanomolar concentration range), potencies (therapeutic index, >1 million), solubility profiles, and dual mechanism of antiviral action that includes two early steps of virus replication prior to the integration of the virus that are considered most important for microbicidal activity.