A Novel Therapeutic for Invasive Candidiasis

侵袭性念珠菌病的新疗法

• 批准号: 8871683
• 负责人: GILL DIAMOND
• 金额: $ 75万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871683
• 关键词: Adverse effects; Antifungal Agents; Antifungal Antibiotics; Biological Assay; Blood; Candida; Candida albicans; Candidiasis; Clinic; Clinical; Clinical Research; Collaborations; Data; Development; Digestion; Disseminated candidiasis; Dose; Dose Fractionation; Drug Kinetics; Drug resistance; Ensure; Enzymes; Funding; Goals; Health; Hepatocyte; Host Defense; Hour; Human; Immune; In Vitro; Infection; Intramuscular; Kidney; Kinetics; Lead; Liver; Mammalian Cell; Maximum Tolerated Dose; Measures; Membrane; Microbe; Mus; Mycoses; No-Observed-Adverse-Effect Level; Oral candidiasis; Organ; Patients; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Property; Protein Binding; Proteins; Rattus; Research Project Grants; Resistance; Resistance development; Safety; Serial Passage; Series; Serum; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Tissues; Toxic effect; Treatment Protocols; animal efficacy; antimicrobial drug; base; commercialization; cytotoxicity; in vivo; killings; membrane activity; mimetics; mortality; novel; novel therapeutics; receptor; research study; resistance mechanism; resistant strain; subcutaneous

DESCRIPTION (provided by applicant): Systemic fungal infections are increasingly common, especially in immune compromised patients. While new antifungal drugs have been developed, there is still a high mortality associated with these infections, especially those due to Candida albicans, other non-albicans species (NAS). This is due to the limited spectrum of the drugs, significant side effects, as well as the development of resistance, leading to an increase in drug-resistant strains. Host defense proteins (HDPs) are naturally occurring, broad-spectrum antimicrobial agents that have been examined recently for their utility as therapeutic antibiotics and antifungals. Chief among their strengths is that microbes do not generally develop resistance to these agents. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. We have demonstrated the potent activity of a series of inexpensive non-peptidic oligomers and compounds that mimic HDPs in both structure and activity against clinical strains of C. albicans associated with oral candidiasis, both in vitro and in vivo. Our preliminary data demonstrate similar antifungal activity for several mimetics against clinical isolates of C. albicans in the presence of human serum and one of these compounds was robustly efficacious in a mouse of disseminated candidiasis. We believe these compounds can form the basis for the development of novel therapies against systemic fungal infections. Our goal is to identify a safe and efficacious HDP mimic(s) as a development lead for treatment of disseminated candidiasis.

描述（由申请人提供）：全身性真菌感染越来越常见，尤其是在免疫功能低下的患者中。尽管已经开发出新的抗真菌药物，但与这些感染相关的死亡率仍然很高，尤其是由白色念珠菌和其他非白色念珠菌物种 (NAS) 引起的感染。这是由于药物谱有限、副作用显着以及耐药性的产生，导致耐药菌株增加。宿主防御蛋白 (HDP) 是天然存在的广谱抗菌剂，最近对其作为治疗性抗生素和抗真菌剂的用途进行了研究。它们的主要优点是微生物通常不会对这些试剂产生耐药性。不幸的是，它们的生产成本昂贵，并且通常对蛋白酶消化敏感。我们已经在体外和体内证明了一系列廉价的非肽寡聚物和化合物的有效活性，这些寡聚体和化合物在结构和活性上均模仿 HDP，对抗与口腔念珠菌病相关的白色念珠菌临床菌株。我们的初步数据表明，在人血清存在下，几种模拟物对白色念珠菌临床分离株具有类似的抗真菌活性，其中一种化合物对患有播散性念珠菌病的小鼠非常有效。我们相信这些化合物可以成为开发针对系统性真菌感染的新疗法的基础。我们的目标是确定一种安全有效的 HDP 模拟物作为治疗播散性念珠菌病的开发先导药物。

项目成果

Antifungal Potential of Host Defense Peptide Mimetics in a Mouse Model of Disseminated Candidiasis.

宿主防御肽模拟物在播散性念珠菌病小鼠模型中的抗真菌潜力。

• 发表时间: 2018-02-27
• 作者: Chowdhury, Mobaswar Hossain;Ryan, Lisa Kathleen;Cherabuddi, Kartikeya;Freeman, Katie B;Weaver, Damian G;Pelletier, Jeffry C;Scott, Richard W;Diamond, Gill
• 通讯作者: Diamond, Gill

Potent in vitro and in vivo antifungal activity of a small molecule host defense peptide mimic through a membrane-active mechanism.

小分子宿主防御肽模拟物通过膜活性机制具有有效的体外和体内抗真菌活性。

• 发表时间: 2017
• 影响因子: 4.6
• 作者: Menzel, Lorenzo P;Chowdhury, Hossain Mobaswar;Masso;Ruddick, William;Falkovsky, Klaudia;Vorona, Rafael;Malsbary, Andrew;Cherabuddi, Kartikeya;Ryan, Lisa K;DiFranco, Kristina M;Brice, David C;Costanzo, Michael J;Weaver, Dami
• 通讯作者: Weaver, Dami