Development of Small Antimicrobial Peptide Mimics as Drug-Resistant and Susceptib

开发具有耐药性和敏感性的小抗菌肽模拟物

基本信息

批准号：
8725573
负责人：
RICHARD W SCOTT
金额：
$ 100万
依托单位：
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725573
关键词：
Acute Adverse effects Adverse reactions Animals Antibiotics Antimalarials Antimicrobial Resistance Antiparasitic Agents Bacteria Benchmarking Bioavailable Biological Assay Biological Availability Cell membrane Cells Cessation of life Chemicals Chemistry Chloroquine Cholesterol Clinical Clinical Trials Cryptosporidium Cytolysis Data Development Disease Dose Drug Design Drug Formulations Drug Interactions Drug Kinetics Drug or chemical Tissue Distribution Drug resistance Enzymes Exhibits Food Goals Grant Hepatocyte Host Defense Human Immune system Immunocompromised Host In Vitro Incidence Individual Infection Inhibitory Concentration 50 Laboratories Lead Libraries Liver Malaria Measures Membrane Modeling Molecular Multi-Drug Resistance Mus Mutate No-Observed-Adverse-Effect Level Oral Outcome Parasite resistance Parasitemia Parasites Parasitic Diseases Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Phospholipids Plasma Plasmodium falciparum Process Property Protein Binding Proteins Protozoa Quantitative Structure-Activity Relationship Rattus Regimen Relapse Reporting Resistance Resistance development Rodent Safety Scheme Series Site Specificity Staphylococcal Infections Structure-Activity Relationship Synthesis Chemistry Testing Therapeutic Therapeutic Uses Toxic effect Toxoplasma Translating Vacuole Work Yeasts analog animal efficacy antimicrobial antimicrobial peptide base biodefense combat cost cytotoxicity design dosage efficacy testing fungus improved in vivo innovation insight killings lead series member mouse model novel novel strategies pathogenic bacteria receptor research study resistant strain safety study scale up screening therapeutic development treatment duration

项目摘要

DESCRIPTION (provided by applicant): Malaria is a global disease causing > 500 million clinical cases and > 1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is crucial to discover new classes of drugs for anti-malarial drug design to combat resistant parasites. We propose that antimicrobial peptides (AMPs) may provide the basis of a novel class of antimalarials. AMPs are an essential component of the innate immune system. AMPs display very broad- spectrum action against bacteria, yeast, fungus by specifically disrupting their membranes rather than targeting proteins. Antiparasitic activities are also reported for a number of AMPs and are thought to kill protozoa by a mechanism similar to their mechanism of action against bacteria: interacting with plasma membranes, causing excessive permeability, lysis and death. Specificity for the parasite versus host cell is attributed to differences in phospholipid content and the lack of cholesterol in the protozoan membranes. Importantly, the site of action for AMPs is the plasma membrane and not any specific receptors or intracellular protein targets that can easily mutate to escape drug inhibition. Thus, the development of resistance to AMPs is less likely to occur. However, while AMPs have good antimicrobial activity, problems with tissue distribution and toxicity have presented obstacles to translating this expensive class of peptides into drugs. PolyMedix has developed series of small non-peptidic mimics of these AMPs (SMAMPs), which have robust, broad- spectrum activity against bacteria and markedly lower toxicity in animals. We propose SMAMPs may provide the basis of a novel class of antimalarials against which resistance will be intrinsically difficult to develop. SMAMPs from PolyMedix were tested and several kill Pl. falciparum parasites in culture having submicromolar IC50s and low cytotoxicity. Importantly, the top hits are active against both chloroquine-sensitive and resistant parasite lines. Our hypothesis is that they act through the perturbation of the food vacuole and possibly other parasitic membranes resulting in the rapid lysis of the food vacuole and parasite death. Membrane targets in bacteria for antimicrobials have been associated with a lower likelihood for developing resistance and this will be tested in Pl. falciparum. The goal of this grant is to validate and pursue antimalarial SMAMPs for therapeutic development. The Phase I portion generates proof-of-concept for this class of compounds through in vitro and in vivo efficacy testing. The Phase II segment aims to result in a discovery lead therapeutic candidate(s). Targeting parasite membranes using SMAMPs represents a highly innovative and novel approach to treating parasitic diseases and distinguishes this project from others in the field. Malaria is a global disease causing at least 500 million clinical cases and more than 1 million deaths each year. Moreover, drug resistant Plasmodium falciparum has become a major problem. Therefore, it is paramount to discover new classes of drugs for anti- malarial drug design to combat resistant parasites. We propose to develop novel antimalarial therapeutics using small non-peptidic mimics of naturally-occurring antimicrobial peptides. These therapeutics should prove to be potent, active against resistant parasites and display a low incidence of resistance.

描述（由申请人提供）：疟疾是一种全球性疾病，每年导致超过 5 亿临床病例和超过 100 万人死亡。此外，耐药性恶性疟原虫已成为一个主要问题。因此，发现新的抗疟药物设计以对抗耐药寄生虫至关重要。我们认为抗菌肽（AMP）可能为一类新型抗疟药提供基础。 AMP 是先天免疫系统的重要组成部分。 AMP 通过特异性破坏细菌、酵母和真菌的细胞膜而不是靶向蛋白质，对细菌、酵母和真菌表现出非常广谱的作用。据报道，许多 AMP 具有抗寄生虫活性，并且被认为通过与细菌作用机制类似的机制杀死原生动物：与质膜相互作用，导致过度渗透、裂解和死亡。寄生虫与宿主细胞的特异性归因于磷脂含量的差异和原生动物膜中缺乏胆固醇。重要的是，AMP 的作用位点是质膜，而不是任何可以轻易突变以逃避药物抑制的特定受体或细胞内蛋白质靶标。因此，不太可能发生对 AMP 的耐药性。然而，虽然 AMP 具有良好的抗菌活性，但组织分布和毒性问题阻碍了将这类昂贵的肽转化为药物。 PolyMedix 开发了一系列这些 AMP (SMAMP) 的小型非肽模拟物，它们具有强大的广谱抗菌活性，并且对动物的毒性显着降低。我们认为 SMAMP 可能提供一类新型抗疟药的基础，对该类抗疟药本质上很难产生耐药性。来自 PolyMedix 的 SMAMP 进行了测试，有几种杀死了 Pl。培养中的恶性疟原虫具有亚微摩尔 IC50 和低细胞毒性。重要的是，热门产品对氯喹敏感和耐药的寄生虫株系均有效。我们的假设是，它们通过扰动食物泡和可能的其他寄生虫膜起作用，导致食物泡快速裂解和寄生虫死亡。抗菌药物细菌的膜靶标与产生耐药性的可能性较低有关，这将在 PI 中进行测试。恶性疟原虫。这笔赠款的目的是验证和追求抗疟 SMAMP 的治疗开发。第一阶段部分通过体外和体内功效测试为此类化合物提供概念验证。 II 期阶段的目标是发现领先的治疗候选药物。使用 SMAMP 靶向寄生虫膜代表了一种高度创新和新颖的治疗寄生虫疾病的方法，并使该项目与该领域的其他项目区分开来。疟疾是一种全球性疾病，每年造成至少 5 亿临床病例和超过 100 万人死亡。此外，耐药性恶性疟原虫已成为一个主要问题。因此，发现用于抗疟药物设计以对抗耐药寄生虫的新型药物至关重要。我们建议使用天然存在的抗菌肽的小型非肽模拟物来开发新型抗疟疗法。这些疗法应该被证明是有效的，能够有效对抗耐药性寄生虫，并且耐药性发生率低。