Design of Potent Peptide Mimetics of Brain-derived Neurotrophic Factor

Abstract

Brain-derived neurotrophic factor (BDNF) has potential for the treatment of human neurodegenerative diseases. However, the general lack of success of neurotrophic factors in clinical trials has led to the suggestion that low molecular weight neurotrophic drugs may be better agents for therapeutic use. Here we describe small, dimeric peptides designed to mimic a pair of solvent-exposed loops important for the binding and activation of the BDNF receptor, trkB. The monomer components that make up the dimers were based on a monocyclic monomeric peptide mimic of a single loop of BDNF (loop 2) that we had previously shown to be an inhibitor of BDNF-mediated neuronal survival (O'Leary, P. D., and Hughes, R. A. (1998) J. Neurochem. 70, 1712-1721). Bicyclic dimeric peptides behaved as partial agonists with respect to BDNF, promoting the survival of embryonic chick sensory neurons in culture. We reasoned that the potency and/or efficacy of these compounds might be improved by reducing the conformational flexibility about their dimerizing linker. Thus, we designed a highly conformationally constrained tricyclic dimeric peptide and synthesized it using an efficient, quasi-one-pot approach. Although still a partial BDNF-like agonist, the tricyclic dimer was particularly potent in promoting neuronal survival in vitro (EC 50 11 pM). The peptides described here, which are greatly reduced in size compared with the parent protein, could serve as useful lead compounds for the development of true neurotrophic drugs and indicate that the structurebased design approach could be used to obtain potent mimetics of other growth factors that dimerize their receptors.

Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents

“…Previous studies have characterized synthetic peptides modeled on loop regions of BDNF, with the goal of using active peptides to derive active non-peptide small molecules that might function as BDNF mimetics (24,53,54). In each of these studies, peptides with neurotrophic activity were found; however, the ability to activate TrkB was either not described (24,53) or not detected (54). Hence whether such peptides can function as ligands that activate TrkB remains to be determined.…”

Design of a Conformationally Defined and Proteolytically Stable Circular Mimetic of Brain-derived Neurotrophic Factor

“…We have previously described a structurebased design approach that has successfully yielded potent mimics of BDNF (23). Bicyclic dimeric peptides, consisting of a pair of disulfide-constrained mimics of loop 2 of BDNF tethered by either a disulfide or amide link, act as BDNF-like partial agonists in vitro, promoting the survival of chick sensory neurons in culture.…”

A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

“…However, clinical trials using recombinant BDNF have been disappointingly negative (6), presumably because of poor delivery, short half-life, and other limitations. Although efforts have been made to circumvent these problems (7,8), no exogenous agents have been identified that act as potent and selective in vivo agonists of TrkB.…”