title: 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.
authors.affiliation: Department of Chemistry, University of Texas at El Paso , 500 West University Avenue, CCSB #3.0302, El Paso, Texas 79968, United States.
authors.forename: Edison
authors.identifier: 0000-0003-2954-9462
authors.initials: E
authors.lastname: Castro
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso , 500 West University Avenue, El Paso, Texas 79968, United States.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Martinez
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso , 500 West University Avenue, El Paso, Texas 79968, United States.
authors.forename: Chang-Soo
authors.identifier: 0000-0001-9426-9534
authors.initials: CS
authors.lastname: Seong
authors.affiliation: Department of Chemistry, University of Texas at El Paso , 500 West University Avenue, CCSB #3.0302, El Paso, Texas 79968, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cabrera-Espinoza
authors.affiliation: Department of Chemistry, University of Texas at El Paso , 500 West University Avenue, CCSB #3.0302, El Paso, Texas 79968, United States.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Department of Chemistry, University of Texas at El Paso , 500 West University Avenue, CCSB #3.0302, El Paso, Texas 79968, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hernandez Garcia
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso , 500 West University Avenue, El Paso, Texas 79968, United States.
authors.forename: Federico
authors.initials: F
authors.lastname: Valdez
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso , 500 West University Avenue, El Paso, Texas 79968, United States.
authors.forename: Manuel
authors.initials: M
authors.lastname: Llano
authors.affiliation: Department of Chemistry, University of Texas at El Paso , 500 West University Avenue, CCSB #3.0302, El Paso, Texas 79968, United States.
authors.forename: Luis
authors.identifier: 0000-0003-1107-9423
authors.initials: L
authors.lastname: Echegoyen
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D037741:Fullerenes / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D002412:Cations; D037741:Fullerenes; D017320:HIV Protease Inhibitors; C000620334:N,N-dimethyl(70)fulleropyrrolidinium Iodide; D011759:Pyrrolidines; D016333:HIV Protease