title: Novel thrombopoietin mimetic peptides bind c-Mpl receptor: Synthesis, biological evaluation and molecular modeling.
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.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yaquan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Tian
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Dejuan
authors.initials: D
authors.lastname: Zhi
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: zhaochy07@lzu.edu.cn.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
authors.affiliation: School of Life Science, Lanzhou University, Lanzhou 730000, China. Electronic address: zhaocy0225@hotmail.com.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
mesh_terms: D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D053628:Receptors, Thrombopoietin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D053628:Receptors, Thrombopoietin; C515728:thrombopoietin mimetic peptide; C082218:MPL protein, human
keywords: Molecular modeling; Thrombopoietin mimetic peptide; c-Mpl receptor