Control of viral-host membrane fusion with hydrogen bond surrogate-based artificial helices
The present invention relates to a peptide having one or more stable, internally-constrained HBS α-helices, where the peptide mimics at least a portion of a class I C-peptide helix or at least a portion of a class I N-peptide helix of a viral (e.g., HIV-I) coiled-coil assembly. Methods of inhibiting viral infectivity of a subject by administering these peptides are also disclosed.
1. A peptide having a stable, internally-constrained alpha-helix, wherein said alpha helix is constrained by a crosslink formed by a carbon-carbon bond-forming reaction, and further wherein the peptide mimics at least a portion of a gp41 C-peptide helix derived from human immunodeficiency virus, wherein the peptide is an inhibitor of viral infectivity, and wherein the peptide comprises the amino acid sequence of SEQ ID NO: 9, and has an internally-constrained alpha-helix spanning residues 1 through 4 of SEQ ID NO: 9.
2. The peptide of claim 1 , wherein the carbon-carbon bond-forming reaction is metathesis.
3. The peptide according to claim 1 , wherein the peptide mimics the WWI region of the gp41 C-peptide helix.
4. The peptide according to claim 1 , wherein the peptide comprises the formula:
wherein
is a single or double carbon-carbon bond;
is a single bond and is cis or trans when is a double bond;
n is 1 or 2;
m is zero or any positive integer;
R is hydrogen, an amino acid side chain, an alkyl group, or an aryl group;
R 1 is an amino acid side chain, an alkyl group, or an aryl group;
R 2 is an amino acid, second peptide, —OR, —CH 2 NH 2 , an alkyl group, an aryl group, hydrogen, or a group having a formula
where R 4 is an amino acid, third peptide, —OR, —NH 2 , an alkyl group, or an aryl group; and R 3 is a fourth peptide.
5. A pharmaceutical composition comprising a peptide according to claim 1 and a pharmaceutically acceptable vehicle.