DEVELOPMENT OF TOPICAL ANTIVIRAL AGENTS FOR TREATING MOLLUSCUM CONTAGIOSUM

 描述（由申请人提供）：传染性软疣（MC）是一种高度接触性皮肤病，由痘病毒（MCV）引起。MC表现为身体和面部的病变，可持续数月至数年才消退。病变最常发生在儿童（5%）和免疫功能低下的个体（5-18%）。感染仅限于皮肤，而不是全身性的。传播直接通过人与人接触、自身接种（抓挠）或间接接触传播，毛巾目前的治疗可能是痛苦的，导致疤痕，色素沉着和心理困扰，特别是对儿童和父母。目前包括一系列物理、化学和药物干预的治疗方法都没有被统一接受或FDA批准。没有专门针对MC开发的药物，因为MCV不能在任何类型的培养细胞中生长以测试新化合物。我们已经取得了四个重大突破。首先，我们已经确定了一个新的蛋白质靶点MCV（mD 4），这是病毒复制所必需的。mD 4是一种持续合成因子，它与其异源二聚体伴侣mA 20一起将病毒聚合酶与模板连接，以合成长链DNA。第二，我们发现了4种具有不同支架的小分子抑制剂，它们靶向mD 4 PF并在体外阻断长链DNA合成。第三，我们构建了一种新的感染性牛痘杂合病毒（mD 4-VV），其表达mD 4靶蛋白，并且被所有4种化合物抑制感染细胞。mD 4-VV杂合病毒是MC药物开发的一个重大进展，因为它提供了第一个基于细胞的系统，用于在痘病毒感染的细胞中筛选针对必需MCV靶蛋白（mD 4）的治疗剂。第四，我们现在已经证明了替代杂交病毒（mD 4-VV）可以感染3-D人类皮肤器官培养物（相当于人类皮肤），并且我们最有效的先导化合物4032在该系统中具有抗病毒活性。因此，我们第一次获得了（1）MCV复制所必需的蛋白质靶标（mD 4），（2）用于优化针对mD 4病毒靶标的类似物的新替代杂交病毒，（3）用于测试抗病毒活性的天然人3-D皮肤器官培养物和（4）具有抗病毒活性的几种化合物。AIMS 1-4是紧密相连的，其中药物化学将在迭代过程中应用，以通过测试抑制和结合的渐进步骤来优化药物疗效和安全性。 靶蛋白、在细胞和人3-D皮肤器官培养物中的有效抗病毒功效、皮肤渗透性和安全性以及在感染mD 4-VV的皮肤小鼠模型中的功效。本阶段II SBIR的具体目标是识别1个或多个适用的高级电极导线 进行IND赋能研究。我们计划的最终目标是提供一种局部皮肤制剂，可以安全快速地解决主要发生在儿童和免疫受损患者中的MC病变。

 DESCRIPTION (provided by applicant): Molluscum contagiosum (MC) is a highly contagious skin disease caused by the poxvirus, MCV. MC appears as lesions on the body and face and can last months-years before resolving. Lesions occur most frequently in children (5%) and immune compromised individuals (5-18%). The infection is confined to skin alone; it is not systemic. Transmission spreads directly from person-person contact, autoinoculation (scratching) or indirect contact e.g., towels. Current treatments can be painful, cause scarring, pigmentation and psychological distress, especially to children and parents. None of the current treatments that include a range of physical, chemical and medicinal interventions are uniformly accepted or FDA approved. No drug has ever been specifically developed for MC because MCV cannot be grown in any type of cultured cell for the purpose of testing new compounds. We have now made FOUR MAJOR BREAKTHROUGHS. FIRST, we have identified a novel protein target in MCV (mD4) that is essential for viral replication. mD4 is a processivity factor, which together with its hetero-dimeric partner mA20, tether the viral Polymerase to the template to enable synthesis of long strands of DNA. SECOND, we have discovered 4 small molecule inhibitors with different scaffolds that target the mD4 PF and block long-chain DNA synthesis in vitro. THIRD, we have constructed a new infectious Vaccinia hybrid virus (mD4-VV) that expresses the mD4 target protein and is inhibited from infecting cells by all 4 compounds. The mD4-VV hybrid virus is a major advancement for MC drug development since it provides the first cell-based system for screening therapeutics against an essential MCV target protein (mD4) in poxvirus-infected cells. FOURTH, we have now shown the surrogate hybrid virus (mD4-VV) can infect 3-D human skin organ cultures (equivalent to human skin), and that our most potent lead compound 4032 has antiviral activity in this system. Thus, for the first-time, we have (1) a protein target (mD4) essential for MCV replication, (2) a new surrogate hybrid-virus for optimizing analogs directed against the mD4 viral target, (3) a natural human 3-D skin organ culture for testing antiviral activity and (4) several compounds with antiviral activity. AIMS 1-4 are tightly interconnected in which medicinal chemistry will be applied in an iterative process to optimize drug efficacy and safety through progressive steps that test for inhibition and binding to the target protein, potent antiviral efficacy in cell and human 3-D skin organ cultures, skin penetration and safety, and efficacy in a cutaneous mouse model of infection with mD4-VV. The specific goal of this Phase II SBIR will be the identification of 1 or more advanced leads suitable for IND-enabling studies. The ultimate goal of our program is to provide a topical skin formulation that will safely and rapidly resolve MC lesions that occur mainly in children and immune compromised patients.