Development of inhibitors of P. falciparum cGMP dependent protein kinase (PfPKG) for malaria chemoprevention

摘要 疟疾是由原生寄生虫疟原虫引起的。它始于疟原虫的感染 肝脏的子孢子。这一步对于扩大寄生虫数量和随后的 症状性红细胞周期抑制红细胞前感染将预防疟疾病理学， 间日疟原虫复发目前针对红细胞前阶段的药物具有显著的副作用， 贵了因此，迫切需要针对疟原虫红细胞前期阶段的新药物。 我们的科学前提是，恶性疟原虫cGMP依赖性蛋白激酶（PfPKG）的抑制将阻断恶性疟原虫cGMP依赖性蛋白激酶的表达。 红细胞前周期，并阻碍红细胞周期。我们的假设是基于数据表明， (i)PfPKG的化学抑制防止了恶性疟原虫子孢子对组织培养细胞的感染，以及恶性疟原虫对组织培养细胞的感染。 小鼠的伯氏孢子。(ii)伯氏疟原虫PKG的化学或遗传抑制阻断了 侵入的子孢子进入成熟的感染性肝阶段。 我们建议启动药物化学的努力，合成和测试一个新的化学系列PfPKG 抑制剂的来自该系列的验证命中证明了PfPKG相对于其人同源物的体外选择性， 酶活性测定，并对寄生虫有活性。我们提出了一个药物化学的努力， 优化来自该系列的分子以产生具有全细胞活性的有效和PfPKG选择性化合物， 用于小鼠体内测试的可接受的药物性质。

ABSTRACT Malaria is caused by the protozoan parasite, Plasmodium. It begins with the infection by Plasmodium sporozoites of the liver. This step is essential for the expansion of parasite numbers and the subsequent symptomatic erythrocytic cycle. Inhibition of pre-erythrocytic infection will prevent malaria pathology and relapses from P. vivax. Current drugs against pre-erythrocytic stages have significant side-effects or are expensive. Therefore, there is an urgent need for new drugs against pre-erythrocytic stages of Plasmodium. Our scientific premise is that inhibition of P. falciparum cGMP-dependent protein kinase (PfPKG) will block the pre-erythrocytic cycle, and impede the erythrocytic cycle. Our hypothesis is based on data demonstrating that (i) chemical inhibition of PfPKG prevents infection by P. falciparum sporozoites of tissue culture cells, and by P. berghei sporozoites of mice. (ii) Chemical or genetic inhibition of P. berghei PKG blocks development of invaded sporozoites into mature, infectious liver stages. We propose to initiate a medicinal chemistry effort to synthesize and test a new chemical series of PfPKG inhibitors. Validated hits from this series demonstrate in vitro selectivity for PfPKG, over its human homolog, in enzymatic activity assays and are activite against the parasite. We propose a medicinal chemistry effort to optimize molecules from this series to yield potent and PfPKG-selective compounds with whole-cell activity, acceptable pharmaceutical properties for in vivo testing in mice.