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A complementary peptide approach applied to the design of novel semaphorin/neuropilin antagonists
Author(s) -
Williams Gareth,
Eickholt Britta J.,
Maison Patrick,
Prinjha Rabinder,
Walsh Frank S.,
Doherty Patrick
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02950.x
Subject(s) - semaphorin , neuropilin 1 , sema3a , biology , microbiology and biotechnology , neuropilin , peptide , biochemistry , peptide sequence , receptor , gene , cancer research , vascular endothelial growth factor , vegf receptors
Semaphorin 3A can inhibit axonal growth and induce neuronal apoptosis following binding to neuropilin‐1, with the membrane proximal MAM (meprin, A5, mu) domain in neuropilin‐1 playing a key role in the formation of a higher order receptor complex. If functional motifs on semaphorin 3A and/or the MAM domain can be identified, then small‐constrained peptides might be developed as antagonists. We have scored peptide pairs for complementary hydropathy and antisense homology to identify a candidate functional motif in the Ig domain of semaphorin 3A, and in the MAM domain of neuropilin‐1. Synthetic peptides corresponding to these sequences fully inhibit growth cone collapse induced by semaphorin 3A. A number of smaller peptides derived from the parental sequence also inhibited the response, particularly after they were constrained by a disulfide bond. Finally, we have used an algorithm to design a peptide that is a near‐perfect hydropathic complement of the candidate functional site in the MAM domain; this also inhibits the semaphorin 3A response. Thus, an algorithm‐driven methodology has led to the identification of three independent semaphorin 3A antagonists. Semaphorin 3F stimulates growth cone collapse following binding to the closest relative to neuropilin‐1 in the genome, neuropilin‐2. Where tested, the peptides that antagonise semaphorin 3A failed to inhibit the semaphorin 3F response.