Retrocyclins: Circular Defensins Active Against HIV-1

描述（由申请人提供）：最近，我们偶然发现某些环状微防御素，结构上与最近在恒河猴中描述的θ-防御素相关的抗微生物肽，在体外有效抑制HIV-1感染。虽然人类不再产生环状小防御素，但人类骨髓以表达假基因的形式提供了证据，表明这些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，我们重新创造了这种丢失的人类肽，我们将其命名为retrocyclin。Retrocyclin被证明是一种比其恒河猴对应物更有效的抗逆转录病毒药物，有效地防止T和M嗜性HIV-1感染CD 4+细胞。因为它是一个小的（18个残基）和明确的分子，retrocyclin是一个有前途的领导化合物，用于设计局部药物，可用于预防人类HIV-1感染。基于我们的初步研究，我们假设逆转录酶a）通过抑制病毒附着、融合或进入发挥作用; B）将抑制粘膜中的HIV-1感染并在粘膜液中具有活性;以及c）是开发作为局部阴道或直肠杀微生物剂以预防HIV传播的主要候选物。在由免疫学家、逆转录病毒学家和肽化学家组成的多学科团队的帮助下，我们将通过以下方式测试这些假设：1）表征逆转录细胞周期蛋白活性的决定因素，并确定其对HIV-1感染的有效抑制作用的分子靶点，2）通过合理设计和测试逆转录细胞周期蛋白同源物来表征逆转录细胞周期蛋白活性的结构决定因素，和3）测定逆转录细胞周期蛋白和同源物在人体体液中的稳定性。这些发现可以阐明HIV-1天然耐药性的新机制，并促进新型宿主相容性抗逆转录病毒药物的开发，以预防HIV感染。由于研制有效的HIV-1疫苗进展缓慢，迫切需要找到替代预防方法。我们的长期目标是开发预防HIV-1粘膜（特别是阴道或直肠）传播的局部药物所需的基本信息。以含有retrocyclin的乳膏或凝胶的形式提供这类药物，将通过向易受伤害的性伴侣提供一种无形的有效保护手段，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.