Novel thrombopoietin mimetic peptides bind c-Mpl receptor: Synthesis, biological evaluation and molecular modeling. Issue 3 (1st February 2017)

• Record Type: Journal Article
• Authors: Liu, Yaquan; Tian, Fang; Zhi, Dejuan; Wang, Haiqing; Zhao, Chunyan; Li, Hongyu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 3(2017)
• Page Start: 1113
• Page End: 1121
• Publication Date: 2017-02-01
• Subjects: Thrombopoietin mimetic peptide -- c-Mpl receptor -- Molecular modeling; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.12.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Novel peptide mimetics that bind and activate c-Mpl receptor were identified, synthesized and tested for biological activities. TPO receptor was modeled and an atomic-level look at the protein-peptide dynamics was conducive to understand key molecular mechanisms and structural features responsible for peptide binding. Hydrophobic interaction was the driven positive forces for the interaction and the larger distances between the centroids of the P-Helix and P'-Helix, togather with the bigger surface area and volume of peptides generally did great favor to the binding behavior. Abstract: Thrombopoietin (TPO) acts in promoting the proliferation of hematopoietic stem cells and by initiating specific maturation events in megakaryocytes. Now, TPO-mimetic peptides with amino acid sequences unrelated to TPO are of considerable pharmaceutical interest. In the present paper, four new TPO mimetic peptides that bind and activate c-Mpl receptor have been identified, synthesized and tested by Dual-Luciferase reporter gene assay for biological activities. The molecular modeling research was also approached to understand key molecular mechanisms and structural features responsible for peptide binding with c-Mpl receptor. The results presented that three of four mimetic peptides showed significant activities. In addition, the molecular modeling approaches proved hydrophobic interactions were the driven positive forces for binding behavior between peptides and c-Mpl receptor. TPO peptide residues in P7, P13 and P7′ positions were identified by the analysis of hydrogen bonds and energy decompositions as the key ones for benefiting better biological activities. Our data suggested the synthesized peptides have considerable potential for the future development of stable and highly active TPO mimetic peptides.