High-affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor
High-affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor
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DOI：
10.1021/bi034131z
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发表时间：
2003-07-22
期刊：
影响因子：
2.9
通讯作者：
Freire, E
中科院分区：
文献类型：
--
作者：
Nezami, A;Kimura, T;Freire, E
针对病毒或微生物靶点的药物开发通常由于存在自然发生的多态性或耐药突变而复杂化。在疟疾病原恶性疟原虫（Plasmodium falciparum）的食物液泡中，已鉴定出四种相关和必需的蛋白酶：plasmepsin I、II和IV以及组织天冬氨酸蛋白酶（HAP）。由于所有这些酶都与受感染的受害者的血红蛋白降解有关，因此同时抑制这四种酶可以预期导致寄生虫更快地饥饿并延迟耐药性的发生，因为四种酶需要以协调一致的方式发生突变。本研究描述了一种旨在抑制整个plasmepsin家族的适应性抑制剂的设计。适应性抑制剂与家族中的主要靶点结合具有极高的亲和力，并对其余成员保持显著的亲和力。这一目标是通过设计抑制剂对结合位点的保守区域的最强和最特异性的相互作用，以及通过灵活的不对称官能团调节靶标变化来实现的。利用这种方法，我们设计了一种对主要靶点plasmepsin 11具有亚纳摩尔亲和力（0.5 nM）的抑制剂，并且对plasmepsin IV， I和HAP的亲和力没有损失或非常小的损失（K-i比值分别为0.4,7.1和17.7）。抑制剂的核心是一个allophenylnorstatine支架。适应性是由一个不对称的氨基吲哚官能团提供的，该官能团面向结合位点的一个关键可变区域。适应性抑制剂对主要靶点的几种变异表现出高亲和力，有望在感染性疾病的化疗中发挥重要作用。
Drug development against viral or microbial targets is often compounded by the existence of naturally occurring polymorphisms or drug resistant mutations. In the case of Plasmodium falciparum, the etiological agent of malaria, four related and essential proteases, plasmepsin I, II, and IV and the histo-aspartyl protease (HAP), have been identified in the food vacuole of the parasite. Since all of these enzymes are involved in the hemoglobin degradation of infected victims, the simultaneous inhibition of the four enzymes can be expected to lead to a faster starvation of the parasite and to delay the onset of drug resistance, since four enzymes will need to mutate in a concerted fashion. This study describes the design of an adaptive inhibitor intended to inhibit the entire plasmepsin family. Adaptive inhibitors bind with extremely high affinity to a primary target within the family and maintain significant affinity against the remaining members. This objective is accomplished by engineering the strongest and most specific interactions of the inhibitor against conserved regions of the binding site and by accommodating target variations by means of flexible asymmetric functional groups. Using this approach, we have designed an inhibitor with subnanomolar affinity (0.5 nM) against the primary target, plasmepsin 11, and with no loss or a very small loss of affinity against plasmepsin IV, I, and HAP (K-i ratios of 0.4, 7.1, and 17.7, respectively). The core of the inhibitor is defined by an allophenylnorstatine scaffold. Adaptability is provided by an asymmetric amino indanol functional group facing one of the key variable regions in the binding site. Adaptive inhibitors, which display high affinity against several variations of a primary target, are expected to play an important role in the chemotherapy of infectious diseases.