Blockade of HIV transmission represents a key challenge in virology, and a pressing public health need. Multipronged therapeutic approaches offer the most promise for targeting this rapidly-evolving pathogen. Two viral protein targets are integrase, which inserts the reverse-transcribed viral genome into the host cell's DNA, and Vif, which links the cellular antiviral protein APOBEC3G to an E3 ubiquitin ligase, causing its ubiquitination and proteasomal degradation. We previously developed PROTACs (PROteolysis TArgeting Chimeras), which are synthetic molecules that function like Vif by recruiting a target protein to an E3 ligase, leading to proteasomal degradation. Here, we propose a novel, three-pronged anti-HIV approach using a PROTAC to degrade integrase while blocking integrase and Vif functions. In proof-of-concept experiments, we will identify by phage display a ligand for integrase that blocks interaction with the host factor lens epithelium-derived growth factor (LEDGF). Simultaneously, we will optimize fragments of Vif that interact with the cellular proteins Elongin B/C, and Cullin 5, which form the E3 ligase of the Vif pathway. We will then create a heterobifunctional peptide combining these two moieties plus a (D-Arg)8 cell permeability moiety and test it for the ability to (a) bind to both the E3 ligase and integrase in vitro;(b) cause integrase to be ubiquitinated and degraded in cell-free systems and in cultured cells, while blocking integrase-LEDGF and Vif-ABOBEC3G interactions;and (c) decrease HIV transmission in cell culture. The degradation of an essential viral protein coupled with blocking two key host-virus protein interactions represents a new paradigm in anti-HIV drug design, and offers great promise as a therapeutic lead. While current anti-HIV therapeutic strategies have been successful in managing existing infections, new and innovative approaches are needed to block the establishment of the HIV virus in infected cells. In this application, we propose an unconventional chemotherapeutic approach to disrupt HIV transmission. Namely, instead of generating small molecules that simply inhibit the function of a HIV-encoded protein, we propose to induce the degradation of such a protein, thus, eliminating it from cell in order to block its function.
While current anti-HIV therapeutic strategies have been successful in managing existing infections, new and innovative approaches are needed to block the establishment of the HIV virus in infected cells. In this application, we propose an unconventional chemotherapeutic approach to disrupt HIV transmission. Namely, instead of generating small molecules that simply inhibit the function of a HIV-encoded protein, we propose to induce the degradation of such a protein, thus, eliminating it from cell in order to block its function.
|Toure, Momar; Crews, Craig M (2016) Small-Molecule PROTACS: New Approaches to Protein Degradation. Angew Chem Int Ed Engl 55:1966-73|
|Lai, Ashton C; Toure, Momar; Hellerschmied, Doris et al. (2016) Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. Angew Chem Int Ed Engl 55:807-10|
|Lim, Sang Min; Xie, Ting; Westover, Kenneth D et al. (2015) Development of small molecules targeting the pseudokinase Her3. Bioorg Med Chem Lett 25:3382-9|
|Gustafson, Jeffrey L; Neklesa, Taavi K; Cox, Carly S et al. (2015) Small-Molecule-Mediated Degradation of the Androgen Receptor through Hydrophobic Tagging. Angew Chem Int Ed Engl 54:9659-62|
|Buckley, Dennis L; Raina, Kanak; Darricarrere, Nicole et al. (2015) HaloPROTACS: Use of Small Molecule PROTACs to Induce Degradation of HaloTag Fusion Proteins. ACS Chem Biol 10:1831-7|
|Lu, Jing; Qian, Yimin; Altieri, Martha et al. (2015) Hijacking the E3Â Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem Biol 22:755-63|
|Bondeson, Daniel P; Mares, Alina; Smith, Ian E D et al. (2015) Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol 11:611-7|
|Buckley, Dennis L; Crews, Craig M (2014) Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system. Angew Chem Int Ed Engl 53:2312-30|
|Xie, Ting; Lim, Sang Min; Westover, Kenneth D et al. (2014) Pharmacological targeting of the pseudokinase Her3. Nat Chem Biol 10:1006-12|
|Raina, Kanak; Noblin, Devin J; Serebrenik, Yevgeniy V et al. (2014) Targeted protein destabilization reveals an estrogen-mediated ER stress response. Nat Chem Biol 10:957-62|
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