Highly active antiretroviral therapy (HAART) has transformed HIV-1 infection, once a fatal illness, to a manageable chronic condition. The latest HAART regimen uses several classes of antiviral therapeutics and a typical therapy requires a combination of three or more drugs from at least two classes. Drug resistance, severe side effects and difficulties in treatment compliance have brought challenges to the implementation of HAART in clinical settings and indicate the need for additional molecular targets. The first critical step of HIV-1 infection is fusion of viral and target cell membranes mediated by viral envelope glycoprotein. T20/Enfuvirtide is the first and still the only fusion inhibitor approved by FDA. Limitations associated with peptide-based drugs as well as rapid emergence of resistant viruses have restricted its long-term use. A desirable goal is therefore to develop orally availabl small-molecule fusion inhibitors, to overcome the limitations of peptide-based drugs and to increase the range of available classes of HAART therapeutics. A transient conformational state of envelope glycoprotein gp41 is targeted by HIV-1 fusion inhibitors, such as T-20/Enfuvirtide - the first approved entry-inhibiting antiviral drug, and by certain neutralizing antibodies. In this project, we hypothesize that HIV-1 gp41 is a "druggable" target for which we can develop small-molecule fusion inhibitors to block its structural rearrangements required for viral entry. We further hypothesize that small-molecule compounds can mimic peptide-based antiviral drugs or neutralizing antibodies to impede gp41 function and to prevent HIV-1 infection. We will bring recent advances from the vaccine side of HIV-1 research into the search for novel therapeutics. When completed, the project will not only yield drug candidates for clinical testing, but should also provide novel reagents for further dissecting molecular mechanisms of HIV-1 entry. We will pursue the following specific aims: 1) We will develop a structure-based platform for optimizing small-molecule fusion inhibitors targeting a hydrophobic pocket of HIV-1 gp41;2) We will produce potent lead compounds that target the gp41 pocket;3) We will identify small-molecule fusion inhibitors targeting the MPER of HIV-1 gp41.

Public Health Relevance

Highly active antiretroviral therapy (HAART) has transformed HIV-1 infection, once a fatal illness, to a manageable chronic condition. Drug resistance, severe side effects and difficulties in treatment compliance have brought challenges to the implementation of HAART in clinical settings and indicate the need for additional molecular targets. In this project, we propose to use structure-based approaches to develop orally available small-molecule fusion inhibitors targeting HIV-1 entry to further improve the effectiveness of HAART.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI112489-01
Application #
8901482
Study Section
Special Emphasis Panel (ZRG1-ADDT-J (09))
Program Officer
Conley, Tony J
Project Start
2014-08-15
Project End
2015-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$439,583
Indirect Cost
$189,583
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115