Our findings highlight the potential therapeutic relevance of C60 fullerene derivatives to block clinically relevant resistant viruses.
HIV-1 resistant to multiple clinically used protease inhibitors or to the maturation inhibitors DSB and PF-46396 were also potently blocked by compound 1.
We have also demonstrated that the addends on the C60 fullerenes and their regiochemistry have pronounced effects on their anti-HIV-1 activity, beyond simple water solubility effects. The difference in anti-HIV-1 activity between compounds 1, 2, 3, and 4 is completely reliant on the chemical nature of their side chains.
Previously, it has been reported that different regioisomers of 2 exhibit similar HIV-1 inhibitory activity, and it was concluded that the trans-3 compound 1 is more potent than the corresponding cis-3 isomer.
The fact that the regiochemistry influences the anti-HIV-1 activity of these fullerene derivatives is important and is under investigation in our laboratories.
In conclusion, our data indicate that fullerene derivatives affect virion maturation of wild-type HIV-1 and protease- and maturation inhibitor-resistant viruses by impairing viral polyprotein processing through a protease-independent mechanism, a paradigm-shifting finding.
The groundbreaking work of Martinez, Castro, Seong, Cerón, Echegoyen, and Llanoa has laid a strong foundation in our understanding of HIV-1 replication inhibition using fullerene derivatives. The study reveals that out of three initially investigated compounds, fullerene derivatives 1 and 2 showed remarkable antiviral activity against HIV-1 replication in human CD4T cells. Intriguingly, these derivatives did not affect the early stages of the virus's life cycle, thus indicating their specific action on the later stages.
Further analyses demonstrated that while RNA packaging and viral production proceeded normally in these viruses, the fullerene derivatives severely impacted Gag and Gag-Pol processing - crucial elements of virion maturation in the HIV-1 life cycle. More surprisingly, the study unveiled a protease-independent mechanism of action for these fullerenes, as they did not inhibit HIV-1 protease activity even at high doses.
The importance of the C60 fullerene's regiochemistry and addends in its anti-HIV-1 activity further underscores the derivatives' complexity and the need for additional research. The knowledge from this study puts us one step closer to developing a novel class of therapeutics capable of disrupting HIV-1 replication in a new and unique way, thus broadening our treatment options for this stubborn and persistent global health threat.