C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease
C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease
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DOI：
10.1021/ml500245v
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发表时间：
2014-09-01
影响因子：
4.2
通讯作者：
Klein, Christian D.
中科院分区：
文献类型：
--
作者：
Behnam, Mira A. M.;Nitsche, Christoph;Klein, Christian D.
登革病毒蛋白酶是开发抗病毒药物的一个很有前途的靶点。我们在这里描述了一个两步的合理优化，导致发现了有效的抑制剂35与登革热蛋白酶血清型2的纳摩尔结合亲和力（IC 50 = 0.6 μ M，Ki = 0.4 μ M）。首先，在先前报道的典型肽序列（Cap-Arg-Lys-Nle-NH 2）的C-末端位置筛选大量天然和非天然氨基酸。与参比化合物1（Bz-Arg-Lys-Nle-NH 2，IC 50 = 13.3 μ M）相比，观察到掺入C-末端苯甘氨酸的抑制潜力高4倍（化合物9，IC 50 = 3.3 μ M）。第二，我们应用片段合并9与以前报道的噻唑烷二酮肽杂合物33（IC 50 = 2.5 μ M）。这种方法导致两个微摩尔亲和力的寡核苷酸片段融合成20倍更有效的登革热蛋白酶竞争性抑制剂。
Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC50 = 0.6 mu M, K-i = 0.4 mu M). First, a large number of natural and non-natural amino acids were screened at the C-terminal position of the previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH2). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH2, IC50 = 13.3 mu M), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC50 = 3.3 mu M). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC50 = 2.5 mu M). This approach led to the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengue protease.