A complementary peptide approach applied to the design of novel semaphorin/neuropilin antagonists.
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.
Williams
Gareth
G
Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
Eickholt
Britta J
BJ
Maison
Patrick
P
Prinjha
Rabinder
R
Walsh
Frank S
FS
Doherty
Patrick
P
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D005727:Ganglia, Spinal / Q000166:cytology* / Q000187:drug effects; D020439:Growth Cones / Q000187:drug effects*; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000494:pharmacology; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D039921:Neuropilins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors* / Q000737:chemistry
D046911:Macromolecular Substances; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D039921:Neuropilins; D010446:Peptide Fragments; C491230:SEMA3F protein, human; D040121:Semaphorin-3A