Pre-clinical candidate suppresses HIV-1 virus in humanized mice
Researchers from Yale University have developed a new nonnucleoside reverse transcriptase inhibitor (NNRTI), which suppresses the HIV virus, protects immune cells and works synergistically with available HIV medicines.
Researchers from Yale University (CT, USA) used computational and structure-based drug design to develop a series of NNRTIs that target the viral polymerase to suppress HIV infection. The series was refined to boost potency and lower toxicity, leading to identification of a pre-clinical candidate, Compound I. The study, published recently in Proceedings of the National Academy of Sciences, has demonstrated the effectiveness of this promising new drug compound.
The drug candidate was tested in humanized mice, which had transplanted human blood cells and were infected with HIV. In these models, the compound was found to suppress HIV-1 virus to undetectable levels, while also protecting immune cells and working synergistically with approved HIV medicines. The researchers also concluded that the drug was potent in drug-resistant strains of HIV-1 and caused no cytotoxicity or off-target effects.
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Working with a drug delivery expert, the team also developed a method by which the drug could be delivered in a long-acting nanoparticle form. This could enable a single dose of the compound to be effective for almost 3 weeks.
The long-acting compound with low cytotoxicity has the potential to improve HIV treatments. Karen S. Anderson, senior co-author of the study and professor of pharmacology and of molecular biophysics and biochemistry at Yale School of Medicine, explained: "Our drug candidate works synergistically with all current classes of HIV drugs, as well as some that are also being tested in clinical trials. It enhances their potency and could be a better combination medication."
Kudalkar SN, Beloor J, Quijano E, et al. From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. Proceedings of the National Academy of Sciences, (Epub ahead of print) (2017). DOI: 10.1073/pnas.1717932115;