RT info:eu-repo/semantics/article
T1 Promiscuous, multi-target lupane-type triterpenoids inhibits wilild type and drug resistant HIV-1 replication through the interference with several targets
A1 Jiménez Díaz, Ignacio Antonio
A1 Bedoya, Luis M.
A1 Beltrán, Manuela
A1 García-Pérez, Javier
A1 Obregón-Calderón, Patricia
A1 Callies, Oliver
A1 Bazzocchi, Isabel L.
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/915/34815
UL http://riull.ull.es/xmlui/handle/915/34815
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 07-jun-2024