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      https://www.ias.ac.in/article/fulltext/jbsc/044/06/0130

    • Keywords

       

      BMP2-targeted therapy; Bone morphogenetic protein 2; bone disease; computational peptide design; head-totail cyclic peptide

    • Abstract

       

      Human bone morphogenetic protein 2 (BMP2) is a bone-growth regulatory factor involved in the formation of bone andcartilage, and has been recognized as an attractive therapeutic target for a variety of bone diseases and defects. Here, wereport successful design of a head-to-tail cyclic peptide based on crystal structure to target BMP2. Computational alaninescanning identifies two hotspot regions at the crystal complex interface of BMP2 with its type-IA receptor; promising one isstripped from the interface to derive a linear self-inhibitory peptide RPS2[r78-94] that covers residues 78–94 of the receptorprotein. Dynamics simulation and energetics analysis reveal that the peptide is highly flexible in isolated state and cannotspontaneously bind to BMP2. The RPS2[r78-94] peptide is further extended from its N- and C-termini until reaching twospatially vicinal residues 74 and 98 in the crystal structure of intact BMP2–receptor complex system, consequently resultingin a longer peptide RPS2[r74-98], which is then cyclized in a head-to-tail manner to obtain its cyclic counterpartcycRPS2[r74-98]. Computational analysis suggests that the cyclic peptide can well maintain in a conformation similar withits active conformation in complex crystal structure, exhibiting a smaller disorder and a larger potency than its linearcounterpart. Further assays confirm that the two linear peptides RPS2[r78-94] and RPS2[r74-98] are nonbinders of BMP2,whereas, as designed, the cyclic peptide cycRPS2[r74-98] can bind to BMP2 with a moderate affinity. The cyclic peptide isexpected as a lead molecular entity to develop new and potent peptide-based drugs for BMP2-targeted therapy.

    • Author Affiliations

       

      XIAOHUA FAN1 HAI XIA1 XIAOYUN LIU2 BENYING LI3 JUN FANG4

      1. Department of Joint and Trauma Surgery, Yidu Central Hospital, Weifang Medical University, Qingzhou 262500, China
      2. Department of Cardiology, Yidu Central Hospital, Weifang Medical University, Qingzhou 262500, China
      3. Department of Obstetrics, Yidu Central Hospital, Weifang Medical University, Qingzhou 262500, China
      4. Department of Spine Surgery, Yidu Central Hospital, Weifang Medical University, Qingzhou 262500, China
    • Dates

       
  • Journal of Biosciences | News

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