Development of a Peptide-Drug Conjugate for Topically Treating the Viral Skin Disease Molluscum Contagiosum

开发用于局部治疗病毒性皮肤病传染性软疣的肽-药物缀合物

• 批准号: 10257353
• 负责人: ROBERT Paul RICCIARDI
• 金额: $ 30.65万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-19 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257353
• 关键词: Amino Acids; Antiviral Agents; Back; Binding; Biological Assay; Cells; Chemicals; Child; Cicatrix; DNA biosynthesis; Development; FDA approved; Face; Future; Goals; Immune; Immune system; Impairment; In Vitro; Individual; Infection; Intervention; Lead; Lesion; Measurable; Measures; Medical; Metabolic; Molecular Target; Molluscum Contagiosum; Molluscum contagiosum virus; Morbidity - disease rate; Pain; Penetration; Peptides; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physical Sufferings; Plaque Assay; Polymerase; Poxviridae; Preparation; Production; Property; Proteins; Risk; Scanning; Skin; Solubility; Structure; Surface Plasmon Resonance; System; Testing; Topical application; Toxic effect; Viral; Viral Skin Diseases; Virus; Work; analog; base; cytotoxicity; drug development; experience; improved; indexing; peptide drug; protein function; psychological distress; screening; skin disorder; small molecule; tissue culture; transmission process; Amino Acids; Antiviral Agents; Back; Binding; Biological Assay; Cells; Chemicals; Child; Cicatrix; DNA biosynthesis; Development; FDA approved; Face; Future; Goals; Immune; Immune system; Impairment; In Vitro; Individual; Infection; Intervention; Lead; Lesion; Measurable; Measures; Medical; Metabolic; Molecular Target; Molluscum Contagiosum; Molluscum contagiosum virus; Morbidity - disease rate; Pain; Penetration; Peptides; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physical Sufferings; Plaque Assay; Polymerase; Poxviridae; Preparation; Production; Property; Proteins; Risk; Scanning; Skin; Solubility; Structure; Surface Plasmon Resonance; System; Testing; Topical application; Toxic effect; Viral; Viral Skin Diseases; Virus; Work; analog; base; cytotoxicity; drug development; experience; improved; indexing; peptide drug; protein function; psychological distress; screening; skin disorder; small molecule; tissue culture; transmission process

ABSTRACT Molluscum contagiosum (MC) is a highly contagious skin disease caused by the poxvirus, MCV. It remains an Unmet Medical Need due to lack of an approved antiviral drug. MC appears as lesions on the body and face that can last months-years before resolving. Lesions occur most frequently in children (5%) and immune compromised individuals (5-18%). The infection is confined to the epidermal skin layers; it is not systemic. Transmission spreads directly from person-person contact, autoinoculation or indirect contact with fomites. Current treatments can be painful, cause scarring, and psychological distress. None of the current treatments that include a range of physical, chemical and medicinal interventions are uniformly accepted or FDA approved. The reason why no approved drug against MCV has been developed is because the virus cannot be grown in tissue culture for testing. We have now made four major breakthroughs: First, we have identified a protein target (mD4) of MCV that is essential for replication. The mD4 protein functions as a processivity factor (PF) that tethers the viral Polymerase (Pol) to the template to enable continuous synthesis of DNA. Second, we have constructed a mD4- surrogate virus (mD4-VV), providing the first cell-based system for screening compounds against an essential MCV target protein (mD4) in infected cells. Third, we have synthesized a small molecule (7269) that that binds a precise region of the mD4 target protein, causing it to unfold and no longer function. While 7269 can block infection by the surrogate virus, we were unable to improve its potency or eliminate its slight toxicity despite an intense medicinal chemistry campaign. Fourth, we overcame this impasse by conjugating a peptide to produce TriValine-7269 that binds the mD4 with a potency that is 6.3-fold greater than that of unconjugated 7269 and has no measurable toxicity. Since TriValine-7269 does not alter direct binding to the mD4 target, its increased potency is due to cellular penetration and/or stability. The challenge that impedes further drug development is that TriValine-7269 has no related analog of equal or greater potency to mitigate risk in the next stages of drug development. The GOAL is to identify analogs of TriValine-7269 of equal or greater potency as essential backups. AIM 1 will utilize medicinal chemistry to synthesize analogs of TriValine-7269. The focus will be to vary both the Peptide and Linker portions of TriValine-7269. The 7269 portion will not be modified since it has already been optimized. We will produce 30-40 analogs. AIM 2 will evaluate new analogs for antiviral potency against the surrogate virus; cytotoxicity; blocking in vitro processive DNA synthesis; binding to the mD4 target. AIM 3 will evaluate structurally distinct analogs for in vitro ADME activities that are relevant for topical application including metabolic stability, solubility and cell permeability. Conjugates with criteria that exceed or match TriValine-7269 will provide the minimum number of analogs for future drug development.

抽象的 小软体动物（MC）是由Poxvirus，MCV引起的一种高度传染性的皮肤疾病。它 由于缺乏批准的抗病毒药，仍然是未满足的医疗需求。 MC出现为病变 在解决之前可以持续几个月的身体和脸部。病变最常发生在儿童中 （5％）和免疫受损的个体（5-18％）。感染仅限于表皮皮肤层。 它不是系统性的。传播直接从人类接触，自动接种或间接传播 与FOMITE接触。当前的治疗可能会很痛苦，会导致疤痕和心理困扰。没有 包括一系列物理，化学和药用干预措施的当前治疗方法均匀 接受或批准FDA。没有开发针对MCV的批准药物的原因是 因为该病毒不能在组织培养中生长进行测试。我们现在做了四个专业 突破：首先，我们确定了MCV的蛋白质靶标（MD4） 复制。 MD4蛋白充当植物性聚合酶（POL）的加工性因子（PF） 到模板以实现DNA的连续合成。其次，我们构建了一个MD4- 替代病毒（MD4-VV），为筛选化合物提供了第一个基于细胞的系统 感染细胞中必需的MCV靶蛋白（MD4）。第三，我们合成了一个小分子 （7269）结合了MD4靶蛋白的精确区域，导致其展开，不再 功能。虽然7269可以通过替代病毒阻止感染，但我们无法提高其效力或 尽管有强烈的药物化学运动，但仍消除了其轻微的毒性。第四，我们克服了这个 通过结合肽产生三列氨酸7269的僵局，该肽与MD4结合的效力 6.3倍比未缀合的7269倍，没有可测量的毒性。自Trivaline-7269以来 不会改变与MD4靶标的直接结合，其效力提高是由于细胞穿透和/或 稳定。阻碍进一步开发药物的挑战是Trivaline-7269与 在药物开发的下一个阶段，相等或更大的效力的类似物减轻风险。目标是 将同等效力或更高效力的三角氨酸-7269的类似物作为基本备份。 AIM 1将使用 药物化学以合成Trivaline-7269的类似物。重点是改变两种肽 和Trivaline-7269的连接器部分。 7269部分将不会被修改，因为它已经存在 优化。我们将产生30-40个类似物。 AIM 2将评估针对抗病毒效力的新类似物 替代病毒；细胞毒性；阻断体外过程DNA合成；与MD4目标结合。 AIM 3将评估与主题相关的体外ADME活动的结构不同的类似物 应用包括代谢稳定性，溶解度和细胞渗透性。与标准共轭 超过或匹配Trivaline-7269将为未来的药物开发提供最少的类似物数量。