Discovery of Inhibitors of Drug Resistant HIV Proteases
Profile last edited on: 6/1/2009

Total Award Amount
Award Phase
Principal Investigator
Laurence Melnick
Activity Indicator

Company Information

Sunovion Pharmaceuticals Inc (AKA:Sepracor Inc)

84 Waterford Drive
Marlborough, MA 01752
   (508) 481-6700
Multiple Locations:   
Congressional District:   03
County:   Middlesex

Phase I

Phase I year
Phase I Amount
The therapeutic effects of drugs against HIV are overcome by drug resistant HIV variants. We describe a yeast drug resistance 'trap' for discovery by rapid positive selection of drug resistant HIV protease variants. This 'trap' is an adaptation of the yeast interaction trap/two hybrid system (Brent and Ptashne, Cell 43: 729; Fields and Song, Nature 340:245). Transcription of specific reporter genes or selectable marker genes in yeast are to be put under the regulation of a element transcription activator protein. Genetic engineering will be used to construct a hybrid activator gene in which the two activator elements are joined by a segment of HIV pol polyprotein. The HIV portion of the hybrid will include the HIV protease and one or more of its cleavage substrate sites. Activation of transcription by this hybrid activator will be dependent upon the activity of the protease. Media are described which will allow growth of the drug resistance trap yeast cells only if the protease is active or only if the protease is inactive. Large libraries of mutant protease genes will be screened or selected from to discover HIV protease variants which are active despite the presence of protease inhibitory drugs.National Institute of Allergy and Infectious Diseases (NIAID)

Phase II

Phase II year
1997 (last award $$: 1998)
Phase II Amount
We describe the development and coordinated application of molecular biology, combinatorial chemistry and computational science for the development of anti HI-PR inhibitors specifically designed against drug resistant proteases. We demonstrate a unique microbial expression assay that identifies resistance conferring mutations with a striking correspondence to clinically relevant mutations. This assay for resistance has the advantages over mammalian cell culture of speed, reproducibility, exquisite sensitivity and inclusiveness. The expression assay system is also ideal for comparing inhibitors for efficacy against both native and variant proteases and for identifying single inhibitors or combinations for which resistance conferring substitutions occur infrequently. We propose to work in three areas: 1. Synthesis and testing of combinatorial libraries of potential protease inhibitors against native and variant proteases. 2. Computational science and computer modeling for creation of virtual chemical libraries, the modeling of protease variants and the identification of variant inhibitors. 3. Optimization of screening and positive selection techniques for the rapid identification of protease variants and their inhibitors. PROPOSED COMMERCIAL APPLICATION: Discovery of lead compounds for HIV protease therapeutic combinations against resistance. 2. Develop software for predicting changes in proteins that give rise to resistant variants.