Synthesis and structural optimization of oncolytic peptide LTX-315

• Published in: Bioorganic & medicinal chemistry 2024-06, Vol.107, p.117760, Article 117760
• Main Authors: Song, Min, Liu, Qing, Yao, Jing-Fang, Wang, Yu-Tao, Ma, Yan-Nan, Xu, Huan, Yu, Qian-Yao, Li, Zhibo, Du, Shan-Shan, Qi, Yun-Kun
• Format: Article
• Language: English
• Subjects: Anticancer peptides (ACPs); D-type peptides; LTX-315; Oncolytic peptides; Solid-phase peptide synthesis (SPPS); Solid-phase S-alkylation
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2024.117760

The cost-effective synthesis and stability-guided structural optimizations were conducted on LTX-315, and the obtained twenty derived peptides were systematically evaluated for their anticancer potentials. Of noted, the efficient peptide cleavage and solid-phase S‑alkylation were established for the cost effective synthesis of derived peptides. Strikingly, the novel derivative MS-20 was demonstrated to possess significantly high proteolytic stability, sustained anticancer durability, and drastically reduced synthesis costs. [Display omitted] •The cost-effective synthesis and stability-guided structural optimizations were conducted on the oncolytic peptide LTX-315.•The efficient solid-phase S‑alkylation was established for the site-selective modification of anticancer peptides.•Twenty LTX-315 derived-peptides were efficiently synthesized and evaluated for their anticancer potentials.•The peptide MS-20 exhibited the high proteolytic stability, sustained anticancer durability, and reduced synthesis costs.•Dip-to-Cys(Dpm) and L-type-to-D-type amino acid substitutions are promising strategies for the optimization of LTX-315. Oncolytic peptides represented potential novel candidates for anticancer treatments especially drug-resistant cancer cell lines. One of the most promising and extensively studied is LTX-315, which is considered as the first in class oncolytic peptide and has entered phase I/II clinical trials. Nevertheless, the shortcomings including poor proteolytic stability, moderate anticancer durability and high synthesis costs may hinder the widespread clinical applications of LTX-315. In order to reduce the synthesis costs, as well as develop derivatives possessing both high protease-stability and durable anticancer efficiency, twenty LTX-315-based derived-peptides were designed and efficiently synthesized. Especially, through solid-phase S-alkylation, as well as the optimized peptide cleavage condition, the derived peptides could be prepared with drastically reduced synthesis cost. The in vitro anticancer efficiency, serum stability, anticancer durability, anti-migration activity, and hemolysis effect were systematically investigated. It was found that derived peptide MS-13 exhibited comparable anticancer efficiency and durability to those of LTX-315. Strikingly, the D-type peptide MS-20, which is the enantiomer of MS-13, was demonstrated to possess significantly high proteolytic stability and sustained anticancer durability. In general, the cost-ef