Rational design of type-IA receptor-derived cyclic peptides to target human bone morphogenic protein 2

Human bone morphogenetic protein 2 (BMP2) is a bone-growth regulatory factor involved in the formation of bone and cartilage, and has been recogn ized as an attractive therapeutic target for a variety of bone diseases and defects. Here, we report successful design of a head-to-tail cyclic peptide based on crystal structure to target BMP2. Computational alanine scanning identifies two hotspot regions at the crystal complex interface of BMP2 with its type-IA receptor; promising one is stripped from the interface to derive a linear self-inhibitory peptide RPS2^[r78-94] that covers residues 78-94 of the receptor protein. Dynamics simulation and energetics analysis reveal that the peptide is highly flexible in isolated state and cannot spontaneously bind to BMP2. The RPS2^[r78-94] peptide is further extended from its N- and C-termini until reaching two spatially vicinal residues 74 and 98 in the crystal structure of intact BMP2-receptor complex system, consequently resulting in a longer peptide RPS2^[r74-98], which is then cyclized in a head-to-tail manner to obtain its cyclic counterpart cycRPS2^[r74-98]. Computational analysis suggests that the cyclic peptide can well maintain in a conformation similar with its active conformation in complex crystal structure, exhibiting a smaller disorder and a larger potency than its linear counterpart. 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 is expected as a lead molecular entity to develop new and potent peptide-based drugs for BMP2-targeted therapy.