微管蛋白
化学
微管
肽
立体化学
抗有丝分裂剂
螺旋(腹足类)
生物物理学
生物化学
细胞生物学
生物
生态学
蜗牛
作者
Anindyasundar Adak,Gaurav Das,Varsha Gupta,Juhee Khan,Nabanita Mukherjee,Prasenjit Mondal,Rajsekhar Roy,Surajit Barman,Prabir Kumar Gharai,Surajit Ghosh
标识
DOI:10.1021/acs.jmedchem.2c01116
摘要
Protein-protein interactions play a crucial role in microtubule dynamics. Microtubules are considered as a key target for the design and development of anticancer therapeutics, where inhibition of tubulin-tubulin interactions plays a crucial role. Here, we focused on a few key helical stretches at the interface of α,β-tubulin heterodimers and developed a structural mimic of these helical peptides, which can serve as potent inhibitors of microtubule polymerization. To induce helicity, we have made stapled analogues of these sequences. Thereafter, we modified the lead sequences of the antimitotic stapled peptides with halo derivatives. It is observed that halo-substituted stapled peptides follow an interesting trend for the electronegativity of halogen atoms in interaction patterns with tubulin and a correlation in the toxicity profile. Remarkably, we found that para-fluorophenylalanine-modified stapled peptide is the most potent inhibitors, which perturbs microtubule dynamics, induces apoptotic death, and inhibits the growth of melanoma.
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