TY - JOUR
T1 - New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains
AU - Nalli, Marianna
AU - Armijos Rivera, Jorge I
AU - Masci, Domiziana
AU - Coluccia, Antonio
AU - Badia, Roger
AU - Riveira-Muñoz, Eva
AU - Brambilla, Alessandro
AU - Cinquina, Elisabetta
AU - Turriziani, Ombretta
AU - Falasca, Francesca
AU - Catalano, Myriam
AU - Limatola, Cristina
AU - Esté, José A
AU - Maga, Giovanni
AU - Silvestri, Romano
AU - Crespan, Emmanuele
AU - La Regina, Giuseppe
N1 - Copyright © 2020 Elsevier Masson SAS. All rights reserved.
PY - 2020/8/11
Y1 - 2020/8/11
N2 - We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N-Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N-Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N-Y181C RTs to binary and ternary complexes, respectively.
AB - We designed and synthesized 21 new indolylarylsulfones (IASs) as new HIV-1 NNRTIs. Among these, IAS 12 exhibited a remarkable antiviral activity against single and double mutants (K103N EC50 = <0.7 nM; Y181C EC50 = <0.7 nM; Y188L EC50 = 21.3 nM; K103N-Y181C EC50 = 6.2 nM), resulting equally or more active than previuosly reported IAS 6 and some approved anti-HIV-1 drugs. Docking and molecular dynamics simulations of compound 12 in complex with WT, Y181C, Y188L, K103N and K103N-Y181C RTs clarified a general binding mode that was consistent with biological results. Kinetic experiments disclosed that derivative 12 preferentially binds WT and K103N-Y181C RTs to binary and ternary complexes, respectively.
U2 - 10.1016/j.ejmech.2020.112696
DO - 10.1016/j.ejmech.2020.112696
M3 - Article
C2 - 32883642
VL - 208
SP - 112696
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -