Jun Xu , Jiahui Xu , Jianguang Lu , Yuanzhen Dong , Xue Feng , Yapeng Wang , Hongxiang Zhu , Chengcheng Wang , Jun Feng
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引用次数: 0
Abstract
Thrombopoietin (TPO) mimetic peptides activate c-Mpl receptor-mediated signaling to stimulate platelet production, possessing similar bioactivity to endogenous TPO. However, their clinical application is limited by rapid clearance in vivo (t₁/₂ ≈ 1 h). To address this limitation, various long-acting modification strategies, such as PEGylation and Fc fusion, have been extensively developed. In this study, we designed a new molecule by integrating two long-acting technologies with complementary mechanisms: (1) fatty acid conjugation to enhance albumin binding, and (2) XTENylation to increase hydrodynamic radius. The novel TPO mimetic peptide demonstrated comparable in vitro activity (0.12 ± 0.076 nM vs. romiplostim 0.10 ± 0.026 nM) and comparable in vivo platelets elevating efficacy in normal mice to romiplostim while exhibiting superior pharmacokinetic properties: prolonged elimination half-life (10.86 ± 0.36 h vs. 2.93 ± 0.05 h in controls) and elevated maximum plasma concentration (184.57 ± 64.00 ng/mL vs. 93.22 ± 60.99 ng/mL in controls). These findings validate the synergistic efficacy of dual-mechanistic modifications and provide a novel strategy for developing next-generation TPO therapeutics with tunable pharmacokinetic profiles.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.