Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease
Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease
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DOI：
10.1016/j.antiviral.2012.02.008
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发表时间：
2012-04-01
影响因子：
7.6
通讯作者：
Klein, Christian D.
中科院分区：
文献类型：
--
作者：
Nitsche, Christoph;Behnam, Mira A. M.;Klein, Christian D.
针对登革病毒和相关黄病毒的新的化疗药物在抗病毒药物开发中的兴趣越来越大。病毒丝氨酸蛋白酶NS2B-NS3是开发这类药物的一个有前途的靶标。目前还没有对靶标具有高亲和力的这种蛋白水解酶的类药物抑制剂。目前的工作描述了新的复古二肽和三肽杂交物的发现，这种杂交物不一定需要亲电的“弹头”来实现低微摩尔范围的亲和力。该系列中最活跃的序列是R-Arg-Lys-NLE-NH2三肽。通过N-端基(R)的变化，可以表明前面描述的芳基氰基丙烯酰胺部分是该位置上的优选基团。复古三肽杂交物比复古二肽杂交物更具活性和选择性。在凝血酶和西尼罗河病毒蛋白酶的反筛选中可以显示对登革病毒蛋白水解酶的显著选择性。与含有D-赖氨酸和D-精氨酸残基的反向序列相似，R-Arg-Lys-NLE-NH2的替代序列对登革病毒蛋白水解酶没有较高的亲和力。与已知抑制剂抑肽酶的竞争实验结果表明，这类化合物的N-末端芳基氰基丙烯酰胺残基结合在酶的催化中心附近。(C)2012爱思唯尔B.V.保留所有权利。
New chemotherapeutics against Dengue virus and related flaviviruses are of growing interest in antiviral drug discovery. The viral serine protease NS2B-NS3 is a promising target for the development of such agents. Drug-like inhibitors of this protease with high affinity to the target are not available at the moment. The present work describes the discovery of new retro di- and tripeptide hybrids that do not necessarily require an electrophilic "warhead" to achieve affinities in the low micromolar range. The most active sequence in this series is the tripeptide R-Arg-Lys-Nle-NH2. By variation of the N-terminal groups (R) it could be shown that the previously described arylcyanoacrylamide moiety is a preferable group in this position. Retro tripeptide hybrids were found to be more active and more selective than retro dipeptide hybrids. A significant selectivity towards the Dengue virus protease could be shown in a counterscreen with thrombin and the West Nile virus protease. Alternative sequences to R-Arg-Lys-Nle-NH2 did not have higher affinities towards the Dengue virus protease, similar to retro-inverse sequences with D-lysine and D-arginine residues. The results of a competition assay with the known inhibitor aprotinin indicate that the N-terminal arylcyanoacrylamide residue of this compound class binds near the catalytic center of the enzyme. (c) 2012 Elsevier B.V. All rights reserved.