Characterization of SPP inhibitors suppressing propagation of HCV and protozoa
Characterization of SPP inhibitors suppressing propagation of HCV and protozoa
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DOI：
10.1073/pnas.1712484114
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发表时间：
2017-12-12
影响因子：
11.1
通讯作者：
Matsuura, Yoshiharu
中科院分区：
文献类型：
--
作者：
Hirano, Junki;Okamoto, Toru;Matsuura, Yoshiharu
信号肽肽酶（SPP）是一种膜内天冬氨酸蛋白酶，参与丙型肝炎病毒（HCV）核心蛋白的成熟。据报道，SPP对HCV核心蛋白的加工在HCV的繁殖和致病中起关键作用。在这里，我们研究了γ-分泌酶，另一种膜内裂解蛋白酶，对SPP的抑制活性的抑制剂，我们的研究结果表明，在γ-分泌酶抑制剂的二苯并氮杂卓型结构是至关重要的SPP的抑制。空间分布表明，具有二苯并氮杂卓结构的γ-分泌酶抑制剂化合物YO-01027通过与SPP中的Val 223的相互作用，在体外和体内均表现出对SPP的有效抑制活性。与直接作用的抗病毒药物治疗相反，用这种SPP抑制剂治疗抑制了所有HCV基因型的核心蛋白的成熟，而没有出现耐药病毒。YO-01027还有效地抑制原生动物如恶性疟原虫和刚地弓形虫的繁殖。这些数据表明，SPP是一个理想的目标，不仅对慢性丙型肝炎的治疗，而且对原生动物的发展。
Signal peptide peptidase (SPP) is an intramembrane aspartic protease involved in the maturation of the core protein of hepatitis C virus (HCV). The processing of HCV core protein by SPP has been reported to be critical for the propagation and pathogenesis of HCV. Here we examined the inhibitory activity of inhibitors for gamma-secretase, another intramembrane cleaving protease, against SPP, and our findings revealed that the dibenzoazepine-type structure in the gamma-secretase inhibitors is critical for the inhibition of SPP. The spatial distribution showed that the gamma-secretase inhibitor compound YO-01027 with the dibenzoazepine structure exhibits potent inhibiting activity against SPP in vitro and in vivo through the interaction of Val223 in SPP. Treatment with this SPP inhibitor suppressed the maturation of core proteins of all HCV genotypes without the emergence of drug-resistant viruses, in contrast to the treatment with direct-acting antivirals. YO-01027 also efficiently inhibited the propagation of protozoa such as Plasmodium falciparum and Toxoplasma gondii. These data suggest that SPP is an ideal target for the development of therapeutics not only against chronic hepatitis C but also against protozoiasis.