Inhibition of Rhodesain as a Novel Therapeutic Modality for Human African Trypanosomiasis
Inhibition of Rhodesain as a Novel Therapeutic Modality for Human African Trypanosomiasis
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DOI：
10.1021/jm301424d
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发表时间：
2013-07-25
影响因子：
7.3
通讯作者：
Conti, Paola
中科院分区：
文献类型：
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作者：
Ettari, Roberta;Tamborini, Lucia;Conti, Paola
Rhodesain是布氏锥虫的一种类似组织蛋白酶L的半胱氨酸蛋白酶，被认为是治疗人类非洲锥虫病的潜在靶点。最近的研究结果证实，罗得森是一种溶酶体蛋白水解酶，对寄生虫的生存至关重要。布氏毛滴虫需要Rhodesain穿过血脑屏障，降解宿主免疫球蛋白，并翻转布氏毛滴虫不同的表面包膜糖蛋白，这会损害有效的宿主免疫反应。在这一视角下，我们讨论了罗地松抑制剂的主要类别，包括多肽、多肽和非多肽结构，重点是那些在酶亲和力和杀锥虫活性之间表现出最佳匹配的药物，以及那些目前正在进行的前期研究。
Rhodesain, a cathepsin L-like cysteine protease of T. brucei rhodesiense, is considered a potential target for the treatment of human African trypanosomiasis. Recent findings have confirmed that rhodesain, a lysosomal protease, is essential for parasite survival. Rhodesain is required by T. brucei to cross the blood-brain barrier, degrade host immunoglobulins, and turn over variant surface coat glycoproteins of T. brucei, which impair effective host immune responses. In this Perspective, we discuss the main classes of rhodesain inhibitors, including peptidic, peptidomimetic, and nonpeptidic structures, emphasizing those that have exhibited an optimal match between enzymatic affinity and trypanocidal profile and those for which predinical investigations are currently in progress.