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In Vivo Targeted Degradation of HIV Proteins


Fast Track proposals will be accepted
Number of anticipated awards: 1-2
Budget (total costs, per award):
 Phase I: up to $300,000 for up to one year; Phase II: up to $2,000,000 for up to 3 years



Antiretroviral drugs are effective in controlling an HIV infected person’s viral load by inhibiting the fusion of the virus to a CD4 T-cell or inhibiting HIV enzymes such as reverse transcriptase, integrase and protease.  The success of these drugs is dependent on their ability to bind to a reactive site on their target. Attempts to generate small molecule inhibitors to other HIV proteins have been difficult since they lack a reactive site that can bind a small molecule.  This leaves multiple HIV expressed proteins in an infected cell as “undruggable”.  Targeting therapeutics to one or more HIV proteins may be an effective way of shutting down viral replication, preventing cellular transmission and ultimately lead to a sustained viral remission.

Newly developed methods have demonstrated the ability of specially prepared reagents to harness the ubiquitin proteasome system for the degradation of targeted proteins.  Reagents can be prepared to bind specifically to proteins without the need of a reactive site.  This technology can be expanded to HIV expressed proteins in an infected cell and ultimately target them for degradation in the proteasome.  Current strategies which target HIV proteins with a small molecule are limited to the inhibition of a single function.  However, the total elimination of an HIV protein from an infected cell would remove all of its biological functions and provide a more thorough consideration of its importance in HIV infectivity. 

Project Goals

The goal of this contract solicitation is to support the development of reagents that specifically bind to HIV expressed proteins in an infected cell and deliver them to the proteasome for degradation.

Phase I activities may include:

  • Designing, optimizing and testing strategies for both targeting HIV proteins and degrading HIV proteins through the ubiquitin proteasome system
  • Performing proof-of-concept of HIV protein degradation in cell lines
  • Evaluating off-target effects
  • Performing proof-of-concept studies in an HIV animal model

Phase II activities may include:

  • Optimizing delivery to target HIV infected cells with minimal off target effects
  • Evaluating in nonhuman primates’ organ toxicity, immune responses/adverse events and pharmacokinetic/pharmacodynamic parameters
  • Performing IND-enabling studies in consultation with the FDA
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