Making benznidazole a better drug for Chagas disease

项目摘要/摘要 治疗克氏锥虫感染有两种非常广泛使用和有效的药物--苯硝唑和 硝呋莫司。虽然这两种药物在宿主体内实现寄生虫治愈的条件尚不确定 -由于很难检测到克氏锥虫，特别是在慢性感染的宿主中-这些化合物可以 实现治愈是没有争议的。这项建议的目的是确定为什么苯硝唑(BZ)未能达到完全 在某些情况下的感染控制，并基于这些结果，走向开发更好的方案 这种治疗将产生更高的成功率。BZ是一种高效药物，能迅速杀死绝大多数T。 克雷兹在宿主体内用单剂治疗。然而，持续治愈感染需要40天的 用“BZ敏感菌株”治疗，但不能治愈“耐BZ菌株”感染。这些数据表明，在 在感染克氏锥虫期间的任何一次，宿主细胞内都有寄生虫，无论是什么原因，都无法接触到 毒品。在这项建议中要检验的主要假设是，既需要长疗程的治疗，也可以 克氏毛滴虫对大多数菌株的治愈以及部分菌株对BZ诱导治愈的抗性，是由于T。 克鲁兹病毒可以入侵药物无法接触到的宿主细胞。另一种假设是，T. 克鲁兹病毒在被感染的宿主中处于休眠状态，因此对药物不敏感，也将进行探索。根据机制不同 对于体内对BZ治疗的耐药性，该项目还将探索将提高BZ治疗成功率的方案 既有BZ敏感株又有BZ耐药株，同时还最大限度地减少了给药剂量，从而减少了潜在的 用于不良事件。更好地治疗恰加斯病的最快途径是优化已知的、 像BZ这样的高效药物。该项目将实现这一目标，同时还将生成有关 克氏毛滴虫感染的生物学将有助于指导开发更好的治疗方案和更高的 有效的药物。

Project Summary/Abstract There are two very widely used and effective drugs for the treatment of Trypanosoma cruzi infection - benznidazole and nifurtimox. Although the conditions under which these 2 drugs actually achieve parasitological cure in hosts is uncertain - due to the difficulty of detection T. cruzi, particularly in chronically infected host - the fact that these compounds can achieve cure is not debated. The purpose of this proposal is to determine why benznidazole (BZ) fails to achieve full infection control in some cases and based on these results, move toward the development of better protocols of treatment that will yield a much higher success rate. BZ is a highly effective drug, and rapidly kills the vast majority of T. cruzi in a host with a single dose of treatment. Nevertheless, consistent cure of the infection requires 40 days of treatment with "BZ-sensitive strains and fails to cure infection with "BZ-resistant" strains. These data suggest that at any one time during T. cruzi infection, there are parasites within host cells that are, for whatever reason, inaccessible to drug. The primary hypothesis to be tested in this proposal is that both the requirement of a long course of treatment for cure of T. cruzi with most strains and the resistance of some strains to BZ-induced cure, is due to the propensity of T. cruzi to invade host cells that are inaccessible to drug. The alternative hypothesis, that a subset of the population of T. cruzi in infected hosts is dormant and as a result insensitive to drug, will also be explored. Depending on the mechanism of in vivo resistance to BZ treatment, this project will also explore protocols that will improve treatment success rate for both BZ-sensitive and BZ-resistant T. cruzi strains while also minimizing dosage of drug delivered and thus the potential for adverse events. The most rapid path to better treatments for Chagas disease is to optimize the delivery of known, highly effective drugs such as BZ. This project will accomplish that goal while also generating basic information on the biology of T. cruzi infection that will help guide the development of even better treatment protocols and more highly effective drugs.