AI Article Synopsis
- Oral antiretroviral medications are crucial for treating millions with HIV and can also prevent new infections, but many treatment-experienced patients face limited options due to drug resistance and adherence issues.
- GS-6207 is a promising new long-acting antiretroviral that disrupts the HIV capsid protein's function, showing high potency and potential for extended effectiveness through subcutaneous injections.
- Phase-1 studies indicate that a single dose of GS-6207 significantly reduces viral load in patients for over six months, supporting its role as a long-acting treatment or prevention method for HIV.
Article Abstract
Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188729 | PMC |
| http://dx.doi.org/10.1038/s41586-020-2443-1 | DOI Listing |
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