Viral membrane fusion occurs at the point immediately prior to the viral infection of a cell. The fusion event is promoted by specific proteins on the surface of the virus. In influenza, the protein primarily responsible for the fusion event is hemagglutin. This protein binds to sialic acid residues on the surface of the host protein. Once bound, the host protein engulfs the virus into an endosome. In the endosome, the pH drops to about 4. This acidic environment promotes a conformational change in hemagluttin. What was once a hydrophobic core becomes an exposed peptide which interacts with the host cell lipid bilayer, allowing the membranes to fuse and the virus to expel it's genome into the host cell. Though hemagglutin is probably the best characterized viral membrane fusion protein, many fusion events take place at neutral pH. An example of neutral pH fusion is the viral membrane fusion event that takes place prior to and during HIV infection. This question has been addressed by using a solubl form of an avian retroviral glycoprotein. This protein needs to recognize a host cell membrane receptor, termed Tva, in order to fuse to that given membrane. Tva appears to contain within it a single repeat of the widespread motif from the low density lipoprotein receptor(LDLR). This motif is critical for viral infectivity. Furthermore, it has been shown that a 19 residue peptide derived from Tva is sufficient to promote lipid binding in a lipid binding assay, which is an indication of a fusgenic conformation having been adopted. Using the crystal structure of the LDLR motif, we are designing small peptides and/or peptide-mimetics that will act like the LDLR from Tva in promoting the switch of the retroviral Env protein to it's fusogenic state. The resources in the Computer Graphics Laboratory for structure manipulation and visualization should prove very helpful in designing these molecules.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-22
Application #
6119102
Study Section
Project Start
1999-07-01
Project End
2000-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
22
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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