(2S)-氰基吡咯烷脯氨酰内肽酶抑制剂对二肽基肽酶-IV 的抑制作用

IF 1.1 4区 化学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Russian Journal of Bioorganic Chemistry Pub Date : 2024-12-16 DOI:10.1134/S1068162024060281
G. I. Makarov, N. N. Zolotov, V. F. Pozdnev
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引用次数: 0

摘要

目的:脯氨酰内肽酶(PEP)和二肽基肽酶 IV(DPP4)是丝氨酸肽酶,可在脯氨酸残基的羧基上裂解肽。这些酶参与许多生理过程的调节,参与神经肽和肽类激素的产生、修饰和利用。我们发现,X-Y-2-S-氰基吡咯烷通式(其中 X 是保护基团,Y 是除甘氨酸和脯氨酸以外的任何氨基酸)的化合物也能抑制 DPP4。为了解释这些化合物抑制 DPP4 的意外能力,我们着手从结构上深入分析它们与 PEP 和 DPP4 活性位点的相互作用。方法:为了实现这一目标,我们合成了一系列 2-S-氰基吡咯烷的 N 保护氨基酸衍生物,测定了它们对 PEP 和 DPP4 的抑制常数,并对这些复合物的结构进行了分子动力学建模。结果与讨论如果 X 是苄氧羰基或琥珀酰基保护基团,Y 不是甘氨酸或脯氨酸残基,即带有侧链的 L-氨基酸残基,则 X-Y-2-S 吡咯烷 PEP 抑制剂可抑制 DPP4。其中,N-苄氧羰基氨基-L-蛋氨酰-2S-吡咯烷-2-甲腈具有明显的抗失眠活性。分子动力学模型显示,抑制剂中蛋氨酸或色氨酸残基的大疏水侧链可确保其与 DPP4 的活性位点结合,弥补 N 保护基团产生的立体阻碍。结论:通过分子动力学建模方法,我们确定了 2-S-氰基吡咯烷氨基酸衍生物的结构与其抑制 DPP4 的能力之间的关系。这为创造新药、影响正常情况下和各种病理过程中调节功能系统的肽能环节开辟了前景。
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Inhibition of Dipeptidylpeptidase-IV by (2S)-Cyanopyrrolidine Inhibitors of Prolyl Endopeptidase

Objective: Prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DPP4) are serine peptidases, cleaving peptides at the carboxyl group of proline residues. These enzymes are involved in the regulation of many physiological processes, participating in the production, modification, and utilization of neuropeptides and peptide hormones. We found that compounds of the X-Y-2-S-cyanopyrrolidine general formula, where X is a protecting group and Y is any amino acid other than glycine and proline, which are PEP inhibitors, also inhibit DPP4. To explain the unexpected ability of these compounds to inhibit DPP4, we set out to develop a structurally reasoned insights of their interaction with the PEP and DPP4 active sites. Methods: To achieve this goal, we synthesized a series of N-protected amino acid derivatives of 2-S-cyanopyrrolidine, determined their inhibition constants for PEP and DPP4, and performed molecular dynamics modeling of the structures of these complexes. Results and Discussion: X-Y-2-S-pyrrolidine PEP inhibitors can inhibit DPP4, if X is a benzyloxycarbonyl or succinyl protecting group and Y is not a glycine or proline residue, i.e., they are L-amino acid residues with side chains. Among them, N-benzyloxycarbonylamino-L-methionyl-2S-pyrrolidine-2-carbonitrile has pronounced antiamnesic activity. Molecular dynamics modeling showed that the large hydrophobic side chain of methionine or tryptophan residues in the inhibitor ensures its binding to the active site of DPP4, compensating for steric hindrance created by the N-protecting group. Conclusions: Using molecular dynamics modeling methods, we established a relationship between the structure of 2-S-cyanopyrrolidine amino acid derivatives and their ability to inhibit DPP4. This opens the prospect of creating new drugs, affecting the peptidergic link in the regulation of functional systems in normal conditions and in various pathological processes.

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来源期刊
Russian Journal of Bioorganic Chemistry
Russian Journal of Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
1.80
自引率
10.00%
发文量
118
审稿时长
3 months
期刊介绍: Russian Journal of Bioorganic Chemistry publishes reviews and original experimental and theoretical studies on the structure, function, structure–activity relationships, and synthesis of biopolymers, such as proteins, nucleic acids, polysaccharides, mixed biopolymers, and their complexes, and low-molecular-weight biologically active compounds (peptides, sugars, lipids, antibiotics, etc.). The journal also covers selected aspects of neuro- and immunochemistry, biotechnology, and ecology.
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