Cyclic Peptide Triazole Dual Site Inhibitors of HIV-1 Envelope gp120 Glycoproteins
Cyclic Peptide Triazole Dual Site Inhibitors of HIV-1 Envelope gp120 Glycoproteins
Globally, there are about 37 million people living with HIV/AIDS and 1.2 million died from AIDS-related illnesses in 2014. In the US, over 1.1 million live with HIV/AIDS and 50,000 new cases are reported each year. The HIV therapeutics market was valued at $14.3 billion in 2012 and is expected to reach $16.3 billion by 2019. Among the most promising types of HIV therapeutics are fusion/entry inhibitors, which work by preventing HIV from infecting host cells. Another highly sought HIV interventional therapy is one that could specifically target and kill infected cells. However, there are currently only two fusion/entry inhibitor-based medicines currently available, and no therapies are known that can specifically target and kill HIV infected cells.
Researchers in the Chaiken lab have developed small cyclic peptide triazoles with a potent affinity and inhibition activity against HIV-1 gp120 envelope proteins. HIV-1 entry into the host cell is mediated by interaction of the gp120/gp41 envelope protein complex with cellular CD4 and chemokine co-receptors CCR5 and CXCR4. The functional activity and proteolytic stability of these cyclic peptides are being validated, including inhibition of cell infection and gp120 shedding from the virus, the latter of which irreversibly inactivates the virus before host cell encounter. These macrocycles also have potential for use in HIV treatment by targeting and selectively killing HIV infected cells.
Applications
- Clear infectious HIV-1 virions by direct irreversible inactivation
- Inhibit HIV-1 infected cells and suppress virus formation by infected cells
- Potential to direct molecule to kill HIV-1 infected cells
- Virolytic agent to prevent viral infection in absence of cells
Advantages
- New candidate of fusion/entry inhibitors for HIV-1 therapy
- Low probability of major drug-to-drug interactions
- Non-toxic to normal cells due to high selectivity to HIV-1 Env gp120
- Highly stable against proteolytic cleavage
- Half-life of at least 24 hours in plasma in some formulations
- Facile scale-up of peptide chemical synthesis
Intellectual Property and Development Status
Issued United States Patent 8,951,963
PCT application pending PCT/US2015/064708
References
Rashad, A.A. et al. Chemical Optimization of Macrocyclic HIV-1 Inactivators for Improving Potency and Increasing the Structural Diversity at the Triazole Ring. Org. Biomol. Chem., 2017.
Aneja R. et al. Peptide triazole inactivators of HIV-1 utilize a conserved two-cavity binding site at the junction of the inner and outer domains of Env gp120. J Med Chem. 2015, 58(9), p.3843-3858.
Rashad A.A. et al. Macrocyclic envelope glycoprotein antagonists that irreversibly inactivate HIV-1 before host cell encounter. J Med Chem. 2015, 58(18), p. 7603-7608.
Chaiken I. and Rashad A.A. Peptide triazole inactivators of HIV-1: how do they work and what is their potential? Future Med Chem. 2015, 7(17), p.2305-2310.
Kamanna K. et al. Non-natural peptide antagonists of HIV-1 envelope gp120. ChemMedChem, 2013, 8(2).