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

描述(申请人提供)：疟疾是一种全球性疾病，每年导致5亿临床病例和100万人死亡。此外，耐药恶性疟原虫已经成为一个主要问题。因此，发现新的抗疟疾药物设计以对抗抗药性寄生虫是至关重要的。我们认为抗菌肽(AMPs)可能是一类新型抗疟疾药物的基础。AMP是先天免疫系统的重要组成部分。AMPS通过专门破坏细菌、酵母和真菌的膜而不是针对蛋白质而显示出非常广泛的抗细菌、酵母和真菌的作用。据报道，一些AMP也具有抗寄生虫活性，被认为通过与其抗细菌作用机制相似的机制杀死原生动物：与质膜相互作用，导致过度渗透、溶解和死亡。寄生虫对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，AMPs的作用部位是质膜，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靶标。因此，对AMPS产生抗药性的可能性较小。然而，虽然AMPs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多肽转化为药物。Polymedix已经开发了这些AMPs(SMAMPs)的一系列小型非肽模拟物，这些AMPs具有强大的、广谱的抗细菌活性，并且对动物的毒性显著降低。我们认为SMAMPs可能提供了一类新的抗疟疾药物的基础，对这些药物的耐药性本质上是难以开发的。对来自Polymedix的SMAMP进行了检测，其中几种可杀死Pl。培养的恶性疟原虫具有亚微摩尔IC50和低细胞毒性。重要的是，最高的命中率对氯喹敏感和抗药性寄生虫株都有效。我们的假设是，它们通过扰乱食物液泡和可能的其他寄生膜来发挥作用，导致食物液泡的快速溶解和寄生虫的死亡。细菌中抗菌素的膜靶标与产生耐药性的可能性较低有关，这将在PL中进行测试。恶性疟原虫。这笔赠款的目标是验证和实施用于治疗开发的抗疟疾SMAMP。第一阶段部分通过体外和体内药效测试为这类化合物产生概念验证。第二阶段旨在产生一位发现领先治疗候选人(S)。利用SMAMPS靶向寄生虫膜是治疗寄生虫病的一种高度创新和新颖的方法，并将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100多万人死亡。此外，耐药恶性疟原虫已经成为一个主要问题。因此，发现新的抗疟疾药物设计以对抗抗药性寄生虫是至关重要的。我们建议使用自然产生的抗菌肽的小非多肽模拟物来开发新的抗疟疾疗法。这些疗法应该被证明是有效的，有效地对抗耐药寄生虫，并显示出低耐药发生率。

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.