Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1

Gambini Luca; Udompholkul Parima; Baggio Carlo; Muralidharan Aruljothi; Kenjic Nikola; Assar Zahra; Perry J. Jefferson P.; Pellecchia Maurizio

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Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1

机译：靶向MCL-1的赖氨酸共价BH3肽的设计，合成和结构表征

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Modulating disease-relevant protein-protein interactions (PPIs) using pharmacological tools is a critical step toward the design of novel therapeutic strategies. Over the years, however, targeting PPIs has proven a very challenging task owing to the large interfacial areas. Our recent efforts identified possible novel routes for the design of potent and selective inhibitors of PPIs using a structure-based design of covalent inhibitors targeting Lys residues. In this present study, we report on the design, synthesis, and characterizations of the first Lys-covalent BH3 peptide that has a remarkable affinity and selectivity for hMcl-1 over the closely related hBfl-1 protein. Our structural studies, aided by X-ray crystallography, provide atomic-level details of the inhibitor interactions that can be used to further translate these discoveries into novel generation, Lys-covalent pro-apoptotic agents.

机译：使用药理学工具调节疾病相关蛋白质相互作用（PPI）是设计新治疗策略的关键一步。然而，多年来，由于界面面积大，以PPI为目标已被证明是一项非常具有挑战性的任务。我们最近的研究发现，利用以赖氨酸残基为靶点的共价抑制剂的基于结构的设计，可能有新的途径来设计有效和选择性的PPI抑制剂。在本研究中，我们报告了第一个Lys共价BH3肽的设计、合成和表征，该肽对hMcl-1具有显著的亲和力和选择性，而不是密切相关的hBfl-1蛋白。我们的结构研究在X射线晶体学的帮助下，提供了抑制剂相互作用的原子级细节，可用于进一步将这些发现转化为新一代Lys共价促凋亡剂。

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《Journal of Medicinal Chemistry》 |2021年第8期|共10页
作者
Gambini Luca; Udompholkul Parima; Baggio Carlo; Muralidharan Aruljothi; Kenjic Nikola; Assar Zahra; Perry J. Jefferson P.; Pellecchia Maurizio;
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Univ Calif Riverside Sch Med Div Biomed Sci Riverside CA 92521 USA;

Univ Calif Riverside Sch Med Div Biomed Sci Riverside CA 92521 USA;

Univ Calif Riverside Sch Med Div Biomed Sci Riverside CA 92521 USA;

Univ Calif Riverside Sch Med Div Biomed Sci Riverside CA 92521 USA;

Univ Calif Riverside Coll Nat &

Agr Sci Dept Biochem Riverside CA 92521 USA;

Cayman Chem Ann Arbor MI 48108 USA;

Univ Calif Riverside Coll Nat &

Agr Sci Dept Biochem Riverside CA 92521 USA;

Univ Calif Riverside Sch Med Div Biomed Sci Riverside CA 92521 USA;

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正文语种 eng
中图分类药学;
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3. Optimized functional and structural design of dual-target LMRAP,a bifunctional fusion protein with a 25-amino-acid antitumor peptide and GnRH Fc fragment [J] . Meng Li, Hanmei Xu, Junzhi Wang 药学学报：英文版 . 2020,第002期
4. Design, Synthesis and Characterization of Novel Sulfonamides Derivatives as Anticancer Agent Targeting EGFR TK, and Development of New Methods of Synthesis by Microwave Irradiation [J] . Souad Akili, Djamila Ben Hadda, Yaser Bitar, 有机化学国际期刊（英文） . 2021,第004期
5. A New Strategy for the Preparation of Peptide-Targeted Radiopharmaceuticals Based on an Fmoc-Lysine-Derived Single Amino Acid Chelate(SAAC).Automated Solid-Phase Synthesis,NMR Characterization,and in Vitro Screening of fMLF(SAAC)G and fMLF[(SAAC-Re(C [J] . Karin A.Stephenson, Jon Zubieta, Sangeeta Ray Banerjee, Bioconjugate Chemistry . 2004,第1期

机译：基于Fmoc-赖氨酸衍生的单氨基酸螯合物（SAAC）的肽靶向放射性药物的制备新策略SAAC-Re（C
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机译：富勒烯-肽-类固醇共价杂合物的设计，合成和表征
7. Design, synthesis, and characterization of fullerene-peptide-steroid covalent hybrids [J] . Mira S. Bjelakovi?, Tatjana J. Kop, Marina Vlaji?, Tetrahedron . 2014,第45期

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机译：树枝状赖氨酸基团抗微生物肽表面活性剂的合成与表征
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机译：Mcl-1（一种重要的癌症靶标）的选择性小分子抑制剂的基于结构的设计和合成
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机译：设计的BH3肽具有高亲和力和特异性在细胞中靶向Mcl-1
11. Design, Synthesis and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl1 [O] . -1

机译：赖氨酸共价BH3靶向MCL1的设计，合成和结构表征
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机译：设计和生产模仿丝氨酸酯酶活性位点的肽，共价结合有机磷中毒soman

Design, Synthesis, and Structural Characterization of Lysine Covalent BH3 Peptides Targeting Mcl-1

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