Fullerene Derivatives Prevent Packaging of Viral Genomic RNA into HIV-1 Particles by Binding Nucleocapsid Protein

• Published in: Viruses 2021-12, Vol.13 (12), p.2451
• Main Authors: Křížová, Ivana, Dostálková, Alžběta, Castro, Edison, Prchal, Jan, Hadravová, Romana, Kaufman, Filip, Hrabal, Richard, Ruml, Tomáš, Llano, Manuel, Echegoyen, Luis, Rumlová, Michaela
• Format: Article
• Language: English
• Subjects: Analysis; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antiviral activity; Complementary DNA; DNA polymerases; fullerene; Fullerenes; Fullerenes - metabolism; Fullerenes - pharmacology; gag Gene Products, Human Immunodeficiency Virus - metabolism; Genome, Viral - drug effects; Genomes; Genomics; HEK293 Cells; HIV; HIV-1; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - metabolism; HIV-1 - physiology; Human immunodeficiency virus; Humans; Hydrophobicity; Infectivity; inhibition; nucleocapsid; Nucleocapsid Proteins - metabolism; Nucleocapsids; Protein Binding; Proteinase; Reverse Transcription; Ribonucleic acid; RNA; RNA packaging; RNA, Viral - metabolism; RNA-directed DNA polymerase; Viral Genome Packaging - drug effects; Virion - metabolism; Virus Uncoating - drug effects
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v13122451

Fullerene derivatives with hydrophilic substituents have been shown to exhibit a range of biological activities, including antiviral ones. For a long time, the anti-HIV activity of fullerene derivatives was believed to be due to their binding into the hydrophobic pocket of HIV-1 protease, thereby blocking its activity. Recent work, however, brought new evidence of a novel, protease-independent mechanism of fullerene derivatives' action. We studied in more detail the mechanism of the anti-HIV-1 activity of , -dimethyl[70]fulleropyrrolidinium iodide fullerene derivatives. By using a combination of and cell-based approaches, we showed that these C derivatives inhibited neither HIV-1 protease nor HIV-1 maturation. Instead, our data indicate effects of fullerene C derivatives on viral genomic RNA packaging and HIV-1 cDNA synthesis during reverse transcription-without impairing reverse transcriptase activity though. Molecularly, this could be explained by a strong binding affinity of these fullerene derivatives to HIV-1 nucleocapsid domain, preventing its proper interaction with viral genomic RNA, thereby blocking reverse transcription and HIV-1 infectivity. Moreover, the fullerene derivatives' oxidative activity and fluorescence quenching, which could be one of the reasons for the inconsistency among reported anti-HIV-1 mechanisms, are discussed herein.