基于功能蛋白设计靶向多肽及小分子化合物：5个神经系统疾病候选药物的设计策略

Design strategies of five candidate drugs for neurological diseases based on functional protein-targeted peptide and small molecule compound development

摘要

目的：肽类化合物具有靶点亲和力强、特异性高、免疫原性低等优势，因此在明确靶点后可通过蛋白片段截短策略获得肽类化合物作为先导化合物，但肽类化合物存在稳定性差、口服生物利用度低、生产成本高等固有局限；相反，小分子具有口服生物利用度高、代谢稳定、生产成本低等优势。因此，通过分析肽类化合物与靶点蛋白的相互作用模式，筛选可模拟其作用方式并保留活性的小分子化合物就变得尤为重要。文章聚焦于阿尔兹海默病等难治性脑部疾病，通过5个典型转化案例，系统阐述了基于功能蛋白获取活性肽类化合物，解析肽类与靶向蛋白的作用模式，进一步获得靶向小分子化合物的研发路径，可为其他药物设计提供参考。

Abstract

Peptide compounds exhibit the advantages of high target affinity，strong specificity，and low immunogenicity. Therefore，after clarifying the therapeutic target，peptide compounds can be obtained as lead compounds via the protein fragment truncation strategy. However，the inherent structural limitations of peptide compounds result in several drawbacks，such as poor stability，low oral bioavailability，and high production costs. In contrast，small-molecule compounds possess the prominent advantages of high oral bioavailability，metabolic stability，and low production costs. Thus，it is particularly important to screen small-molecule compounds that can mimic the action mode of peptides and retain biological activity by analyzing the interaction modes between peptide compounds and target proteins. Focusing on intractable brain diseases such as Alzheimer’s disease，this paper systematically elaborates on the research and development pathway of deriving active peptide compounds from functional proteins，deciphering the interaction modes between peptides and target proteins，and further obtaining targeted small-molecule compounds through five typical transformation cases，which can provide a valuable reference for subsequent compound design.

关键词

肽类化合物 / 小分子化合物 / 结构改造 / 神经系统疾病

Key words

peptide compound / small-molecule compound / structural modification / neurological disorder

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基金资助

国家自然科学基金(82473768)

江苏省自然科学基金(BK20231266)