Research Service (151), VA Medical Center, 3200 Vine Street, Cincinnati, OH 45220 USA.
Curr Med Chem. 2009;16(20):2514-30. doi: 10.2174/092986709788682038.
Pneumocystis remains an important cause of fatal pneumonia (PCP) in HIV patients and other immunocompromised hosts. Preclinical drug discovery for agents active against PCP has been hindered in large part by the lack of a continuous in vitro growth system. Since approval in 1978, the combination of the folic acid synthesis inhibitor combination trimethoprim-sulfamethoxazole has been the primary agent for prophylaxis and therapy. Short term in vitro assays using cell monolayer-based and cell free systems in combination with in vivo studies in rodent models of infection have been the mainstay of candidate screening methods. These systems and their applications are reviewed here. Most strategies have focused on testing compounds already in clinical use, such as dapsone or atovaquone, for activity against Pneumocystis alone or in combination, and as parent compounds for chemical derivation, such as pentamidine and its analogues. Other successes from the bench include primaquine-clindamycin for moderate pneumonia and the family of Beta-glucan synthase inhibitors, which hold promise for clinical use against PCP. Despite the significant obstacles for drug discovery, progress in identifying novel agents has been made with current systems and the promise of future new targets is expected with the annotation of the Pneumocystis genome.
卡氏肺孢子虫仍然是 HIV 患者和其他免疫功能低下宿主致命性肺炎（PCP）的重要原因。针对卡氏肺孢子虫的临床前药物发现受到很大阻碍，主要是因为缺乏连续的体外生长系统。自 1978 年获得批准以来，叶酸合成抑制剂复方磺胺甲恶唑一直是预防和治疗的主要药物。短期的基于细胞单层和无细胞系统的体外检测，结合感染啮齿动物模型的体内研究，一直是候选药物筛选方法的主要手段。本文回顾了这些系统及其应用。大多数策略都集中在测试已经在临床使用的化合物，如氨苯砜或阿托伐醌，针对卡氏肺孢子虫的单独或联合活性，以及作为母体化合物进行化学衍生，如戊烷脒及其类似物。其他来自实验室的成功案例包括治疗中度肺炎的伯氨喹-克林霉素，以及β-葡聚糖合酶抑制剂家族，它们有望在临床上用于治疗卡氏肺孢子虫病。尽管药物发现存在重大障碍，但利用现有系统已经在确定新型药物方面取得了进展，随着卡氏肺孢子虫基因组注释，预计未来会有新的靶点出现。
