Making benznidazole a better drug for Chagas disease

描述（申请人提供）：治疗克氏锥虫感染有两种非常广泛和有效的药物——苯并硝唑和硝呋替莫。尽管这两种药物在宿主体内真正实现寄生虫治疗的条件尚不确定——由于克氏锥虫的检测困难，特别是在慢性感染的宿主体内——但这些化合物可以实现治愈的事实是毋庸置疑的。本应用的目的是确定为什么苯并硝唑（BZ）在某些情况下无法实现完全的感染控制，并基于这些结果，朝着开发更好的治疗方案迈进，这将产生更高的成功率。BZ是一种非常有效的药物，只需一剂治疗就能迅速杀死宿主体内的绝大多数克氏锥虫。然而，感染的持续治愈需要用“bz敏感”菌株治疗40天，而不能治愈“bz耐药”菌株的感染。这些数据表明，在克氏锥虫感染期间的任何时候，宿主细胞内都有寄生虫，无论出于何种原因，药物无法进入。在本应用中需要验证的主要假设是，大多数克氏锥虫菌株需要很长的治疗过程才能治愈，而一些菌株对bz诱导的治愈产生耐药性，这是由于克氏锥虫倾向于侵入药物无法进入的宿主细胞。另一种假设是，受感染宿主体内有一部分克氏锥虫处于休眠状态，因此对药物不敏感，这一假设也将被探讨。根据对BZ治疗的体内耐药机制，该项目还将探索提高BZ敏感和BZ耐药克氏T.菌株治疗成功率的方案，同时最大限度地减少给药剂量，从而减少潜在的不良事件。改善恰加斯病治疗方法的最快速途径是优化已知高效药物（如BZ）的输送。该项目将实现这一目标，同时也将产生关于克氏锥虫感染生物学的基本信息，这将有助于指导开发更好的治疗方案和更有效的药物。

DESCRIPTION (provided by applicant): 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 tat these compounds can achieve cure is not debated. The purpose of this application 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 application 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.