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赫苏肽A及其类似物的抗分枝杆菌和抗疟活性的合成与评价

Synthesis and Evaluation of Antimycobacterial and Antiplasmodial Activities of Hirsutellide A and Its Analogues.

作者信息

Sahile Henok Asfaw, Martínez-Martínez Maria Santos, Dillenberger Melissa, Becker Katja, Imming Peter

机构信息

Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, 06120 Halle, Germany.

Division of Infectious Diseases, Departments of Medicine, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, V6T 1Z3 Canada.

出版信息

ACS Omega. 2020 Jun 9;5(24):14451-14460. doi: 10.1021/acsomega.0c01065. eCollection 2020 Jun 23.

DOI:10.1021/acsomega.0c01065
PMID:32596583
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7315603/
Abstract

Hirsutellide A is nature-derived cyclic hexadepsipeptide with reported antimycobacterial and antiplasmodial activities. To verify its structure, hirsutellide A was synthesized following a solution-phase peptide synthesis approach. A detailed analysis of the H and C NMR spectra of the synthesized compound revealed structural variation from what had been originally assigned for hirsutellide A, despite the use of identical building blocks. This variation occurred at the two -Ile moieties. To investigate the structure-activity relationship, the depsipeptide and peptide analogues of hirsutellide A were prepared and tested for antimycobacterial and antiplasmodial activities. The compounds displayed antiplasmodial potency against 3D7 while showing weak or no activity against H37Rv. The drug-likeness of the series was assessed through absorption, distribution, metabolism, and excretion (ADME) profiling, revealing systematic differences between the pharmacokinetic properties of cyclic hexapeptides and hexadepsipeptides.

摘要

赫氏菌素A是一种天然来源的环状六聚缩肽，具有抗分枝杆菌和抗疟原虫活性。为了验证其结构，采用溶液相肽合成方法合成了赫氏菌素A。对合成化合物的氢核磁共振谱和碳核磁共振谱进行详细分析后发现，尽管使用了相同的构建模块，但该化合物的结构与最初指定的赫氏菌素A结构存在差异。这种差异发生在两个异亮氨酸部分。为了研究构效关系，制备了赫氏菌素A的缩肽和肽类似物，并测试了它们的抗分枝杆菌和抗疟原虫活性。这些化合物对3D7显示出抗疟活性，而对H37Rv显示出弱活性或无活性。通过吸收、分布、代谢和排泄（ADME）分析评估了该系列化合物的类药性质，揭示了环状六肽和六聚缩肽药代动力学性质之间的系统性差异。

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