RT info:eu-repo/semantics/article T1 Promiscuous, Multi-Target Lupane-Type Triterpenoids Inhibits Wild Type and Drug Resistant HIV-1 Replication Through the Interference With Several Targets A1 Bedoya, Luis M. A1 Beltrán, Manuela A1 García Pérez, Javier A1 Obregón Calderón, Patricia A1 Callies, Oliver A1 Jiménez Díaz, Ignacio Antonio A1 López Bazzocchi, Isabel A1 Alcamí, José K1 HIV-1 K1 antiretrovirals K1 maturation K1 triterpenoids K1 lupanes K1 promiscuous compounds K1 multi-target compounds AB Current research on antiretroviral therapy is mainly focused in the development ofnew formulations or combinations of drugs belonging to already known targets.However, HIV-1 infection is not cured by current therapy and thus, new approachesare needed. Bevirimat was developed by chemical modification of betulinic acid, alupane-type pentacyclic triterpenoid (LPT), as a first-in-class HIV-1 maturation inhibitor.However, in clinical trials, bevirimat showed less activity than expected because ofthe presence of a natural mutation in Gag protein that conferred resistance to a highproportion of HIV-1 strains. In this work, three HIV-1 inhibitors selected from a set ofpreviously screened LPTs were investigated for their targets in the HIV-1 replicationcycle, including their maturation inhibitor effect. LPTs were found to inhibit HIV-1 infectionacting as promiscuous compounds with several targets in the HIV-1 replication cycle.LPT12 inhibited HIV-1 infection mainly through reverse transcription, integration, viraltranscription, viral proteins (Gag) production and maturation inhibition. LPT38 did itthrough integration, viral transcription or Gag production inhibition and finally, LPT42inhibited reverse transcription, viral transcription or Gag production. The three LPTsinhibited HIV-1 infection of human primary lymphocytes and infections with proteaseinhibitors and bevirimat resistant HIV-1 variants with similar values of IC50. Therefore,we show that the LPTs tested inhibited HIV-1 infection through acting on different targetsdepending on their chemical structure and the activities of the different LPTs vary withslight structural alterations. For example, of the three LPTs under study, we found thatonly LPT12 inhibited infectivity of newly-formed viral particles, suggesting a direct actionon the maturation process. Thus, the multi-target behavior gives a potential advantageto these compounds since HIV-1 resistance can be overcome by modulating more thanone target. YR 2018 FD 2018 LK http://riull.ull.es/xmlui/handle/915/36065 UL http://riull.ull.es/xmlui/handle/915/36065 LA en DS Repositorio institucional de la Universidad de La Laguna RD 14-oct-2024