Characterization of New Cationic N,N-Dimethyl[70]fulleropyrrolidinium Iodide Derivatives as Potent HIV-1 Maturation Inhibitors

Abstract

HIV-1 maturation can be impaired by altering protease (PR) activity, the structure of the Gag-Pol substrate, or the molecular interactions of viral structural proteins. Here we report the synthesis and characterization of new cationic N,N-dimethyl[70]fulleropyrrolidinium iodide derivatives that inhibit more than 99% of HIV-1 infectivity at low micromolar concentrations. Analysis of the HIV-1 life cycle indicated that these compounds inhibit viral maturation by impairing Gag and Gag-Pol processing. Importantly, fullerene derivatives 2a-c did not inhibit in vitro PR activity and strongly interacted with HIV immature capsid protein in pull-down experiments. Furthermore, these compounds potently blocked infectivity of viruses harboring mutant PR that are resistant to multiple PR inhibitors or mutant Gag proteins that confer resistance to the maturation inhibitor Bevirimat. Collectively, our studies indicate fullerene derivatives 2a-c as potent and novel HIV-1 maturation inhibitors.

Impact of fullerene derivative isomeric purity on the performance of inverted planar perovskite solar cells

“…S5 and S6† show the UV-vis absorption profiles of the three DMEC 70 isomers in chloroform and the structures of the isomers were unambiguously assigned by comparing their UV-vis profiles with those of known C 70 fullerene analogs. 40 …”

Fullerenes in biology and medicine

“…2). 19, 45 Additionally, fullerenes 2 - 6 inhibited HIV-1 viruses resistant to multiple PR and MIs. Although the mechanism of action is not known, it was suggested to be via impairment of virus maturation as a result of a strong interaction with the immature capsid in pull-down experiments.…”

“…Although the mechanism of action is not known, it was suggested to be via impairment of virus maturation as a result of a strong interaction with the immature capsid in pull-down experiments. 19 Fullerene derivatives 2 - 6 were reported to exhibit no cytotoxicity, therefore they are excellent candidates as anti HIV-1 agents. 19, 45 Due to the solubility of [60]fullerene-peptide derivatives, they have also been considered as potential inhibitors of HIV-1 replication.…”

“…19 Fullerene derivatives 2 - 6 were reported to exhibit no cytotoxicity, therefore they are excellent candidates as anti HIV-1 agents. 19, 45 Due to the solubility of [60]fullerene-peptide derivatives, they have also been considered as potential inhibitors of HIV-1 replication. 46 Using drug screening and docking calculations, a database of PI [60]fullerene derivatives and their binding constants were predicted.…”

“…5 Since then, efficient synthetic methods for fullerene functionalization have been developed. 6, 7 Functionalization with bioactive compounds that exhibit affinity to certain nucleic acids, proteins or cell receptors such as peptides 8-10 or saccharides, 11, 12 functionalization with polar or ionic groups such as hydroxyl, 13, 14 carbonyl 15-17 or quaternary ammonium salts, 18, 19 and encapsulation with macromolecules 20, 21 are the most common approaches to synthesize water-soluble fullerene derivatives for biomedical applications. 22-26 …”