Novel Endocytosis Inhibitors Block Entry of HIV-1 Tat into Neural Cells

Many pathogens including viruses enter cells by endocytosis. We identified and evaluated novel endocytosis inhibitors capable of blocking the entry of the HIV-1 Tat protein into neuronal cells and investigated their potential protective properties against Tat-induced neurotoxicity. In this study, the compounds Les-6631 and Les-6633 were synthesized and assessed. The effects of these compounds on the internalization of dextran and the CPP Tat-Cy5 complex in nerve cells were examined. Additionally, the ability of these compounds to protect against oxidative stress and DNA damage induced by the full-length Tat protein was investigated. Les-6631 and Les-6633 were found to inhibit endocytosis better than the classical endocytosis inhibitor chlorpromazine, thereby effectively preventing the entry of the Tat protein into nerve cells. Moreover, compounds demonstrated the capacity to reduce oxidative stress and protect DNA from Tat-induced damage. In a neuro-AIDS model, both compounds proved effective in preventing neurotoxicity associated with HIV-1 infection, indicating its potential for therapeutic applications. Les-6631 and Les-6633 thus can protect cells from the harmful effects of pathogens. Their use in a neuro-AIDS model suggests a potential application in protective therapies for the nervous system in HIV patients.