New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains

Marianna Nalli; Jorge I Armijos Rivera; Domiziana Masci; Antonio Coluccia; Roger Badia; Eva Riveira-Muñoz; Alessandro Brambilla; Elisabetta Cinquina; Ombretta Turriziani; Francesca Falasca; Myriam Catalano; Cristina Limatola; José A Esté; Giovanni Maga; Romano Silvestri; Emmanuele Crespan; Giuseppe La Regina

doi:10.1016/j.ejmech.2020.112696

New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains

Marianna Nalli, Jorge I Armijos Rivera, Domiziana Masci, Antonio Coluccia, Roger Badia, Eva Riveira-Muñoz, Alessandro Brambilla, Elisabetta Cinquina, Ombretta Turriziani, Francesca Falasca, Myriam Catalano, Cristina Limatola, José A Esté, Giovanni Maga, Romano Silvestri, Emmanuele Crespan, Giuseppe La Regina

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Abstract

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.

Original language	English
Pages (from-to)	112696
Journal	European Journal of Medicinal Chemistry
Volume	208
DOIs	https://doi.org/10.1016/j.ejmech.2020.112696
Publication status	E-pub ahead of print - Aug 11 2020

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Nalli, M., Armijos Rivera, J. I., Masci, D., Coluccia, A., Badia, R., Riveira-Muñoz, E., Brambilla, A., Cinquina, E., Turriziani, O., Falasca, F., Catalano, M., Limatola, C., Esté, J. A., Maga, G., Silvestri, R., Crespan, E., & La Regina, G. (2020). New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains. European Journal of Medicinal Chemistry, 208, 112696. https://doi.org/10.1016/j.ejmech.2020.112696

Nalli, M, Armijos Rivera, JI, Masci, D, Coluccia, A, Badia, R, Riveira-Muñoz, E, Brambilla, A, Cinquina, E, Turriziani, O, Falasca, F, Catalano, M, Limatola, C, Esté, JA, Maga, G, Silvestri, R, Crespan, E & La Regina, G 2020, 'New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains', European Journal of Medicinal Chemistry, vol. 208, pp. 112696. https://doi.org/10.1016/j.ejmech.2020.112696

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title = "New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains",

abstract = "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.",

author = "Marianna Nalli and {Armijos Rivera}, {Jorge I} and Domiziana Masci and Antonio Coluccia and Roger Badia and Eva Riveira-Mu{\~n}oz and Alessandro Brambilla and Elisabetta Cinquina and Ombretta Turriziani and Francesca Falasca and Myriam Catalano and Cristina Limatola and Est{\'e}, {Jos{\'e} A} and Giovanni Maga and Romano Silvestri and Emmanuele Crespan and {La Regina}, Giuseppe",

year = "2020",

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doi = "10.1016/j.ejmech.2020.112696",

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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

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 -

New indolylarylsulfone non-nucleoside reverse transcriptase inhibitors show low nanomolar inhibition of single and double HIV-1 mutant strains

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