Retrocyclins: Circular Defensins Active Against HIV-1

描述(申请人提供)：最近，我们偶然发现，某些环状Minidefensins，结构上与最近在恒河猴中描述的theta-Defensins相关的抗菌肽，在体外有效地抑制HIV-1感染。尽管人类不再产生环状迷你芬森蛋白，但人类骨髓以表达的假基因的形式提供了证据，证明这些多肽曾经是我们基因组遗产的一部分。利用其表达的假基因中仍然编码的序列信息，我们重新创建了这个丢失的人源性多肽，我们将其命名为逆周期蛋白。事实证明，逆转录周期素比恒河猴更有效地抗逆转录病毒，有效地预防了T嗜性和M嗜性HIV-1对CD4+细胞的感染。因为它是一种小分子(18个残基)和定义明确的分子，逆转周期素是一种有希望的先导化合物，用于设计可用于预防人类艾滋病毒-1感染的外用药物。根据我们的初步研究，我们假设逆周期素a)通过抑制病毒附着、融合或进入发挥作用；b)将抑制HIV-1在粘膜中的感染并在粘膜液中发挥活性，以及c)是作为局部阴道或直肠杀菌剂以防止HIV传播的主要候选药物。在一个由免疫学家、逆转录病毒学家和一位多肽化学家组成的多学科团队的协助下，我们将通过1)表征逆转周期蛋白活性的决定因素并确定其有效抑制艾滋病毒-1感染的分子靶点(S)，2)通过合理设计和测试逆转周期蛋白同系物来表征逆转周期蛋白活性的结构决定因素，以及3)确定逆转周期蛋白及其同系物在人体体液中的稳定性，从而检验这些假说。这些发现可以阐明对HIV-1自然耐药的新机制，并促进新的、宿主相容的抗逆转录病毒药物的开发，以预防艾滋病毒感染。由于开发有效的HIV-1疫苗的进展缓慢，迫切需要找到替代的预防方法。我们的长期目标是开发所需的基本信息，以开发防止艾滋病毒-1通过粘膜(特别是经阴道或直肠)传播的外用药物。以含有逆转录周期素的乳膏或凝胶的形式提供这种制剂，将通过为脆弱的性伴侣提供一种看不见的有效保护手段来增强他们的能力。

DESCRIPTION (provided by applicant): Recently, we discovered serendipitously that certain circular minidefensins, antimicrobial peptides structurally related to the theta-defensins recently described in rhesus macaques, potently inhibit HIV-1 infection in vitro. Although humans no longer produce circular minidefensins, human bone marrow provides evidence - in the form of an expressed pseudogene - that these peptides were once part of our genomic heritage. Using the sequence information still encoded within its expressed pseudogene, we recreated this lost human peptide which we have named retrocyclin. Retrocyclin proved to be a more effective antiretroviral than its rhesus counterparts, potently preventing infection of CD4+ cells by both T-and M-tropic HIV-1. Because it is a small (18 residue) and well-defined molecule, retrocyclin is a promising lead compound for designing topical agents that can be used to prevent human HIV-1 infections. Based on our preliminary studies, we hypothesize that retrocyclin a) acts by inhibiting viral attachment, fusion or entry; b) will inhibit HIV-1 infection in the mucosa and be active in mucosal fluids, and c) is a leading candidate for development as a topical vaginal or rectal microbicide to prevent HIV transmission. With assistance from a multidisciplinary team of immunologists, retrovirologists, and a peptide chemist, we will test these hypotheses by 1) characterizing determinants of retrocyclin activity and identifying the molecular target(s) for its potent inhibitory effects on HIV-1 infection, 2) characterizing structural determinants of retrocyclin activity through the rational design and testing of retrocyclin congeners, and 3) determining the stability of retrocyclin and congeners in human fluids. Such findings could elucidate novel mechanisms of natural resistance to HIV-1 and promote the development of novel, host-compatible antiretrovirals to prevent HIV infection. Because progress in developing an effective vaccine for HIV-1 has been slow, there is an urgent need to find alternative preventive approaches. Our long term goal is to develop the basic information needed to develop topical agents that prevent mucosal (particularly vaginal or rectal) transmission of HIV-1. Availability of such agents, in the form of retrocyclin-containing creams or gels, would empower vulnerable sexual partners by providing them with an invisible, effective means of protection.