Peptide-β-lactam Inhibitors of Dengue and West Nile Virus NS2B-NS3 Protease Display Two Distinct Binding Modes.,Journal of Medicinal Chemistry

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Peptide-β-lactam Inhibitors of Dengue and West Nile Virus NS2B-NS3 Protease Display Two Distinct Binding Modes.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-24 , DOI: 10.1021/acs.jmedchem.9b00759
Tonko Dražić ₁ , Sara Kopf ₁ , James Corridan ₁ , Mila M Leuthold ₁ , Branimir Bertoša ₂ , Christian D Klein ₁

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The β-lactam ring represents a valuable moiety that can induce covalent binding of an inhibitor to its target. In this study, we explored di- and tripeptides with β-lactam electrophilic warheads as inhibitors of dengue and West Nile virus NS2B-NS3 protease. Tripeptides with a (3S)-β-lactam moiety displayed the highest activity, with IC50 and EC50 values in the lower micromolar range in biochemical and cellular assays. The activity against dengue protease was in general higher than against West Nile virus protease. The compounds were inactive against the off-targets thrombin and trypsin. Liquid chromatography-mass spectrometry experiments revealed that tripeptide-β-lactam inhibitors bind to the protease in two distinct binding modes. Only one binding mode leads to a covalent, but reversible, interaction of the β-lactam ring with the catalytic serine, followed by release of the inhibitor with opened β-lactam ring. The other binding mode leads to the cleavage of the peptide backbone. This observation provides the first experimental evidence that benzyloxyphenylglycine in flaviviral protease inhibitors is positioned in the prime site of the enzyme.

中文翻译：

登革热和西尼罗河病毒NS2B-NS3蛋白酶的肽-β-内酰胺抑制剂表现出两种不同的结合模式。

β-内酰胺环代表有价值的部分，可以诱导抑制剂与其靶标共价结合。在这项研究中，我们探索了具有β-内酰胺亲电战斗部的二肽和三肽作为登革热和西尼罗河病毒NS2B-NS3蛋白酶的抑制剂。具有（3S）-β-内酰胺部分的三肽显示出最高的活性，在生化和细胞分析中IC50和EC50值在较低的微摩尔范围内。对登革热蛋白酶的活性通常高于对西尼罗河病毒蛋白酶的活性。该化合物对脱靶凝血酶和胰蛋白酶无活性。液相色谱-质谱实验表明，三肽-β-内酰胺抑制剂以两种不同的结合方式与蛋白酶结合。只有一种结合模式会导致共价但可逆的 β-内酰胺环与催化丝氨酸相互作用，随后释放具有打开的β-内酰胺环的抑制剂。其他结合方式导致肽主链的裂解。该观察结果提供了第一个实验证据，表明黄病毒蛋白酶抑制剂中的苄氧基苯基甘氨酸位于酶的主要位点。

更新日期：2019-12-25

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