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 Transactivation of Transcription protein (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 cell-penetrating peptide (CPP) Tat-Cy5 complex in nerve cells were examined. In addition, 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 patients with HIV. This study identifies novel rhodadyn-based inhibitors, Les-6631 and Les-6633, which selectively block dynamin's GTPase activity while sparing clathrin-mediated pathways. They effectively inhibit cellular uptake, protect neural cells from HIV-1 Tat-induced oxidative stress, and reduce mitochondrial and DNA damage. Their selective dynamin inhibition and antioxidant properties highlight their therapeutic potential for neurodegeneration and viral infections, offering cell protection without disrupting essential endocytic functions.