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Fullerene Derivatives Strongly Inhibit HIV-1 Replication by Affecting Virus Maturation without Impairing Protease Activity
Zachary S. Martinez, Edison Castro, Chang-Soo Seong, Maira R. Cerón, Luis Echegoyen, Manuel Llanoa
Department of Biological Sciences and Department of Chemistry, University of Texas at El Paso, El Paso, Texas, USA
Antimicrobial Agents Chemotherapy. 2016 Oct; 60(10): 5731–5741
Summary:
Three compounds previously reported to inhibit HIV-1 replication and/or in vitro activity of reverse transcriptase were studied, but only fullerene derivatives 1 and 2 showed strong antiviral activity on the replication of HIV-1 in human CD4T cells.
However, these compounds did not inhibit infection by single-round infection vesicular stomatitis virus glycoprotein G (VSV-G) pseudotyped viruses, indicating no effect on the early steps of the viral life cycle.
In contrast, analysis of single-round infection VSV-G-pseudotyped HIV-1 produced in the presence of compound 1 or 2 showed a complete lack of infectivity in human CD4 T cells, suggesting that the late stages of the HIV-1 life cycle were affected.
Quantification of virion-associated viral RNA and p24 indicates that RNA packaging and viral production were unremarkable in these viruses. However, Gag and Gag-Pol processing was affected, as evidenced by immunoblot analysis with an anti-p24 antibody and the measurement of virion-associated reverse transcriptase activity, ratifying the effect of the fullerene derivatives on virion maturation of the HIV-1 life cycle.
Surprisingly, fullerenes 1 and 2 did not inhibit HIV-1 protease in an in vitro assay at the doses that potently blocked viral infectivity, suggesting a protease-independent mechanism of action.
Highlighting the potential therapeutic relevance of fullerene derivatives, these compounds block infection by HIV-1 resistant to protease and maturation inhibitors.
Conclusion:
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.
Study analysis
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.
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