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

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.

摘要 传染性软疣（MC）是由痘病毒（MCV）引起的高度接触性皮肤病。它 由于缺乏获批的抗病毒药物，仍然是一种未满足的医疗需求。MC表现为 身体和脸可以持续几个月或几年才解决。病变最常发生在儿童 （5%）和免疫受损个体（5-18%）。感染局限于表皮层; 它不是系统性的。传播直接通过人与人之间的接触、自身接种或间接 接触污染物。目前的治疗可能是痛苦的，导致疤痕和心理困扰。没有一 目前的治疗方法包括一系列物理、化学和药物干预措施，都是一致的 接受或FDA批准。尚未开发出针对MCV的批准药物的原因是 因为病毒不能在组织培养中生长以用于测试。我们现在有四个主要的 突破：首先，我们已经确定了MCV的一个蛋白质靶点（mD 4）， 复制的mD 4蛋白作为一种持续合成因子（PF），将病毒聚合酶（Pol） 使DNA的连续合成成为可能。第二，我们构建了一个mD 4- 替代病毒（mD 4-VV），提供了第一个基于细胞的系统，用于筛选抗 感染细胞中必需的MCV靶蛋白（mD 4）。第三，我们合成了一种小分子 （7269）结合mD 4靶蛋白的精确区域，使其解折叠， 功能虽然7269可以阻断替代病毒的感染，但我们无法提高其效力， 消除其轻微的毒性，尽管激烈的药物化学运动。第四，我们克服了这一点。 通过缀合肽以产生三缬氨酸-7269来进行僵局，该三缬氨酸-7269以 6.3-比未结合的7269高1倍，并且没有可测量的毒性。自TriValine-7269 不改变与mD 4靶标的直接结合，其效力增加是由于细胞渗透和/或 稳定阻碍进一步药物开发的挑战是TriValine-7269没有相关的 类似物具有相同或更大的效力，以减轻药物开发下一阶段的风险。目标是 鉴定具有相等或更大效力的三缬氨酸-7269类似物作为必需的备份。AIM 1将利用 药物化学合成TriValine-7269的类似物。重点将是改变两种肽 和TriValine-7269的接头部分。7269部分将不会被修改，因为它已经被 优化我们将生产30-40个类似物。AIM 2将评估新类似物的抗病毒效力， 替代病毒;细胞毒性;阻断体外进行性DNA合成;与mD 4靶点结合。 AIM 3将评估结构上不同的类似物的体外ADME活性，这些活性与局部给药相关。 应用包括代谢稳定性、溶解性和细胞渗透性。与符合以下条件的条件共轭： 超过或匹配TriValine-7269将为未来的药物开发提供最少数量的类似物。