DEVELOPMENT OF RETROCYCLIN MICROBICIDES

逆环素类杀菌剂的开发

• 批准号: 6955868
• 负责人: ALEXANDER MICHAEL COLE
• 金额: $ 19.2万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6955868
• 关键词: AIDS education /prevention; antiAIDS agent; bioengineering /biomedical engineering; biological products; chemoprevention; clinical research; defensins; drug design /synthesis /production; drug screening /evaluation; human immunodeficiency virus 1; human subject; local antiinfective agents; mucosa; receptor binding; topical drug application; virus infection mechanism; virus receptors

Self-applied prophylactic agents to prevent mucosal, particularly vaginal or rectal, transmission of HIV-1 have the advantage of empowering vulnerable receptive partners to take effective measures for their own protection. In our search for molecules that would be ideal templates for microbicide development, we utilized solid-phase peptide synthesis to recreate an evolutionary lost human antimicrobial peptide "retrocyclin" from its remains, a theta-defensin pseudogene. The ability of retrocyclin to potently prevent infection of CD4+ cells by both X4 and R5 HIV-1 was remarkable. Additional studies revealed that retrocyclin inhibits the initial steps in HIV-1 binding and entry as its mode of action. Next-generation analogs of retrocyclin were found to be active against numerous primary isolates from most groups and subtypes of HIV-1. Importantly, we have identified a lead compound, RC-101, that is highly active against HIV-1, non-cytotoxic, and suitable for preclinical development as a topical microbicide. Based on our studies, we have formed several hypotheses about retrocyclins: A) retrocyclins will likely function to inhibit HIV-1 infection in the vaginal mucosa, B) the glycosylated targets of retrocyclins and cyanovirin N, another potent anti-HIV-1 lectin (Project 1), are different and thus their activities may be complementary, and C) retrocyclins are potent antiretroviral agents suitable for further development as topical vaginal microbicides to prevent HIV transmission. To test these hypotheses, we propose to: 1) Construct and characterize next-generation analogs of anti-HIV retrocyclins, 2) Evaluate candidate retrocyclin formulations for anti-HIV-1 activity, stability and cytotoxicity, and 3) Evaluate candidate retrocyclin formulations for biologic efficacy in human vaginal fluid and serum. While it may be speculative to assert that the evolutionary loss of retrocyclin contributed to the susceptibility of humans to HIV-1 infection, retrocyclins are promising leads for designing naturally occuring microbicides that can prevent HIV infections.

HIV-1的自我应用的预防剂，尤其是阴道或直肠的传播，其优势是赋予脆弱的接收伙伴，以采取有效的措施以进行自身保护。在我们寻找将成为菌心发育的理想模板的分子时，我们利用固相肽合成来从其遗物中重现一种进化的人类抗菌肽“逆转录蛋白”，即theta-defensin psefensin psefensin psegudogene。另一个另一个X4和R5 HIV-1逆转录蛋白有效防止CD4+细胞感染的能力非常出色。其他研究表明，逆转录蛋白抑制了HIV-1结合和进入作为其作用方式的初始步骤。发现逆转录蛋白的下一代类似物对大多数组和HIV-1亚型的许多主要分离株具有活性。重要的是，我们已经确定了一种铅化合物RC-101，该化合物对HIV-1，非胞毒性毒性具有很高的活性，并且适用于临床前发育作为局部菌心。基于我们的研究，我们形成了有关逆转录蛋白的几个假设：a）逆转录蛋白可能会起作用可抑制阴道粘膜中的HIV-1感染，b）逆转录蛋白和cyanovirin n的糖基化靶标，因此可能是另一种有效的抗HIV-1 Lectin（Project 1），是不同的，是不同的，是不同的，并且是不同的。 互补和c）倒角蛋白是有效的抗逆转录病毒药物，适合于作为局部阴道杀菌剂进一步发育，以防止HIV传播。为了检验这些假设，我们提出：1）构建和表征抗HIV逆转录蛋白的下一代类似物，2）评估候选候选胞糖蛋白折叠蛋白表述，以抗HIV-1活性，稳定性和细胞毒性，以及3）评估候选候选逆转录蛋白的表述，以评估人类人体阴道和serm serum and serum and serum and serum and serum and serum and serum corlogical效果。虽然可以推测说，逆转录蛋白的进化损失导致了人类对HIV-1感染的敏感性的敏感性，但另一循环蛋白是设计自然造成可预防HIV感染的微生物的有希望的铅。