In the proposed studies, the physical interaction that occurs between the catalytic subunit of HSV polymerase and its processivity factor UL42 will be characterized in detail. A sequence encoding a peptide corresponding to the C-terminal 36 residues of polymerase, which mediate UL42 binding, will be mutagenized and the ability of mutants to bind UL42 will be quantified using a yeast or bacterial two-hybrid system. The helicity Of these peptides and their ability to inhibit processivity will be examined. These studies will characterize the role of the helix-loop-helix structure formed by the C-terminal 36 residues of polymerase in UL42 binding. The region of UL42 between residues 160 and 190 will also be mutagenized and tested for binding activity in a two- hybrid system. The ability of UL42 mutants to stimulate processivity will be determined. These studies will indicate if the polymerase binding site lies within a contiguous region of UL42. The information gained from these studies will be used in the rational design of compounds that inhibit polymerase/UL42 binding. A combinatorial approach to drug discovery will also be taken by using phage display to identify binding inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI010111-02
Application #
2886315
Study Section
Special Emphasis Panel (ZRG5-EVR (02))
Program Officer
Tseng, Christopher K
Project Start
1999-08-01
Project End
Budget Start
1999-08-01
Budget End
1999-11-23
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115