Design and Synthesis of Phosphonoproline-Proline Bioisosteric Mimetics of Proline Dimers: Pseudopeptide Constructs as Potential Inhibitors of the Zn-Metalloprotease PPEP-1 Associated with Clostridioides difficile

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-07-09 Epub Date: 2026-06-11 DOI:10.1021/acsmedchemlett.6c00221

Erick Ivan Martinez Toto, Sofiane Hocine, Jean-Baptiste Garsi, Paul Skrzypczak, Elena Brunstein, Ulrich Baumann* and Stephen Hanessian*,

引用次数: 0

Abstract

The design, synthesis and preliminary inhibitory activity of novel phosphonoproline–proline-containing pseudohexapeptides against PPEP-1, a metalloprotease secreted by Clostridioides difficile, is reported. Remarkably, the P_(R)-configured phosphonoproline–proline hexapeptide bioisostere of the synthetic heptapeptide Ac-EVNPPVP-NH₂ is 1000 times more active than the corresponding P_(S) analogue as measured by a FRET assay, which represents a binding energy of about 12 kJ/mol. Placing an embedded enantiopure phosphonoproline unit to replace a proline within a peptidic construct constitutes a promising venue in the design of proline-containing metalloenzyme inhibitors.

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脯氨酸二聚体的磷酸脯氨酸-脯氨酸生物等构模拟物的设计和合成：与艰难梭菌相关的锌金属蛋白酶PPEP-1的潜在抑制剂的假肽构建物

本文报道了新型含脯氨酸-脯氨酸假六肽的设计、合成及其对艰难梭菌分泌的金属蛋白酶PPEP-1的初步抑制活性。值得注意的是，合成的七肽Ac-EVNPPVP-NH2的P(R)构型磷酸脯氨酸-脯氨酸六肽生物同位体的活性比相应的P(S)类似物高1000倍，其结合能约为12 kJ/mol。在含有脯氨酸的金属酶抑制剂的设计中，利用嵌入的对映纯磷酸脯氨酸单元取代肽结构中的脯氨酸是一个很有前途的研究方向。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.