Modular alpha-helical mimetics with antiviral activity against respiratory syncitial virus.
A 13-residue peptide sequence from a respiratory syncitial virus fusion protein was constrained in an alpha-helical conformation by fusing two back-to-back cyclic alpha-turn mimetics. The resulting peptide, Ac-(3-->7; 8-->12)-bicyclo-FP[KDEFD][KSIRD]V-NH(2), was highly alpha-helical in water by CD and NMR spectroscopy, correctly positioning crucial binding residues (F488, I491, V493) on one face of the helix and side chain-side chain linkers on a noninteracting face of the helix. This compound displayed potent activity in both a recombinant fusion assay and an RSV antiviral assay (IC(50) = 36 nM) and demonstrates for the first time that back-to-back modular alpha-helix mimetics can produce functional antagonists of important protein-protein interactions.
Shepherd
Nicholas E
NE
Centre for Drug Design and Development, Institute for Molecular Bioscience University of Queensland, Brisbane, Qld 407, Australia.
Hoang
Huy N
HN
Desai
Vishal S
VS
Letouze
Eric
E
Young
Paul R
PR
Fairlie
David P
DP
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012136:Respiratory Syncytial Viruses / Q000737:chemistry* / Q000187:drug effects; D013816:Thermodynamics; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology*
D000998:Antiviral Agents; D010446:Peptide Fragments; D014760:Viral Fusion Proteins