Core structure of gp41 from the HIV envelope glycoprotein
AssigneeWhitehead Institute for Biomedical Research
InventorsDavid C. Chan, Deborah Fass, Min Lu, James M. Berger, Peter S. Kim
Life of this patent
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Abstract
Described are the crystal structure of the .alpha.-helical domain of the gp41 component of HIV-1 envelope glycoprotein which represents the core of fusion-active gp41, methods of identifying and designing drugs which inhibit gp41 function and drugs which do so.
Claims4
A method of producing a drug which inhibits interaction of two components of the core of fusion-active HIV-1 envelope gp41, wherein the two components are referred to as N36 peptide trimer and C34 peptide, respectively, comprising identifying a drug or designing a drug which fits into a cavity on the N36 peptide trimer which is:
- (a) lined by Leu-566 of the left N36 helix of FIG. 1 and Leu-565 of the right N36 helix of FIG. 1;
- (b) formed on the left side by sidechains from the left N36 helix, including residues (top to bottom) Val-570, Lys-574 (aliphatic portion) and Gln-577 of FIG. 1;
- (c) formed on the right side by residues Leu-568, Trp-571 and Gly-572 of the right N36 helix of FIG. 1;
- and
- (d) composed on its floor of Thr-569, Ile-573 and Leu-576 of FIG. 1 and which inhibits interaction of the N36 peptide trimer and the C34 peptide of the core of fusion-active HIV-1 envelope gp41, thereby producing a drug which inhibits interaction of the two components of fusion-active HIV-1 envelope gp41.
A method of producing a drug which inhibits interaction of N36 peptide trimer with C34 peptide, wherein N36 peptide trimer and C34 peptide trimer comprise the core of fusion-active HIV-1 envelope gp41, comprising identifying a drug or designing a drug which:
- (a) fits into a cavity on the N36 peptide trimer:
- (1) lined by Leu-566 of the left N36 helix of FIG. 1 and Leu-565 of the right N36 helix of FIG. 1;
- (2) formed on the left side by sidechains from the left N36 helix, including residues (top to bottom) Val-570, Lys-574 (aliphatic portion) and Gln-577 of FIG. 1;
- (3) formed on the right side by residues Leu-568, Trp-571 and Gly-572 of the right N36 helix of FIG. 1;
- and
- (4) composed on its floor of Thr-569, Ile-573 and Leu-576 of FIG. 1;
- (b) mimics the ability of Ile-635, Trp -631 and Trp-628 of the C34 peptide of FIG. 1 to fit into the cavity of (a) and Asp-632 of the C34 peptide of FIG. 1 to form a conserved salt bridge with Lys-574 of the N36 peptide trimer of FIG. 1;
- and
- (c) inhibits interaction of the N36 peptide trimer and the C34 peptide of the core of fusion-active HIV-1 envelope gp41,
- thereby producing a drug which inhibits interaction of the N36 peptide trimer with the C34 peptide trimer which comprise the core of fusion-active HIV-1 envelope gp41.
A method of producing a drug which inhibits interaction of N36 peptide trimer with C34 peptide, wherein N36 peptide trimer and C34 peptide trimer comprise the core of fusion-active HIV-1 envelope gp41, comprising identifying a drug or designing a drug which:
- (a) fits into a cavity on the N36 peptide trimer:
- (1) lined by Leu-566 of the left N36 helix of FIG. 1 and Leu-565 of the right N36 helix of FIG. 1;
- (2) formed on the left side by sidechains from the left N36 helix, including residues (top to bottom) Val-570, Lys-574 (aliphatic portion) and Gln-577 of FIG. 1;
- (3) formed on the right side by residues Leu-568, Trp-571 and Gly-572 of the right N36 helix of FIG. 1;
- and
- (4) composed on its floor of Thr-569, Ile-573 and Leu-576 of FIG. 1;
- (b) mimics the ability of Ile-635, Trp -631 and Trp-628 of the C34 peptide of FIG. 1 to fit into the cavity of (a);
- and
- (c) inhibits interaction of the N36 peptide timer and the C34 peptide of the core of fusion-active HIV-1 envelope gp41,
- thereby producing a drug which inhibits interaction of the N36 peptide trimer with the C34 peptide trimer which comprise the core of fusion-active HIV-1 envelope gp41.
Dependencies are inferred from the claim text.