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; Alberto Brambilla; Elisabetta Cinquina; Ombretta Turriziani; Francesca Falasca; Myriam Catalano; Cristina Limatola; Carlo 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
, Alberto Brambilla
, Elisabetta Cinquina
, Ombretta Turriziani
, Francesca Falasca
, Myriam Catalano
, Cristina Limatola
, Carlo Limatola
, José A. Esté
, Giovanni Maga
, Romano Silvestri
, Emmanuele Crespan
, Giuseppe La Regina^*

^*Corresponding author

University of Rome La Sapienza
Universidad Nacional de Loja
Autonomous University of Barcelona
National Research Council of Italy

Research output: Contribution to journal › Article

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)	112696-112716
Number of pages	21
Journal	European Journal of Medicinal Chemistry
Volume	208
DOIs	https://doi.org/10.1016/j.ejmech.2020.112696
Publication status	Published - 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AIDS
Anti-HIV Agents
Cell Line, Tumor
Drug Design
Drug Synergism
HIV Reverse Transcriptase
HIV-1
Humans
Indoles
Indolylarylsulfone
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Mutation
Non-nucleoside reverse transcriptase inhibitor
Protein Binding
Reverse Transcriptase Inhibitors
Reverse transcriptase
Structure-Activity Relationship
Sulfones
Zidovudine

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10.1016/j.ejmech.2020.112696

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Nalli, M., Armijos Rivera, J. I., Masci, D., Coluccia, A., Badia, R., Riveira-Muñoz, E., Brambilla, A., Brambilla, A., Cinquina, E., Turriziani, O., Falasca, F., Catalano, M., Limatola, C., 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, 112696-112716. 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.",

keywords = "AIDS, Anti-HIV Agents, Cell Line, Tumor, Drug Design, Drug Synergism, HIV Reverse Transcriptase, HIV-1, Humans, Indoles, Indolylarylsulfone, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Mutation, Non-nucleoside reverse transcriptase inhibitor, Protein Binding, Reverse Transcriptase Inhibitors, Reverse transcriptase, Structure-Activity Relationship, Sulfones, Zidovudine, AIDS, Anti-HIV Agents, Cell Line, Tumor, Drug Design, Drug Synergism, HIV Reverse Transcriptase, HIV-1, Humans, Indoles, Indolylarylsulfone, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, Mutation, Non-nucleoside reverse transcriptase inhibitor, Protein Binding, Reverse Transcriptase Inhibitors, Reverse transcriptase, Structure-Activity Relationship, Sulfones, Zidovudine",

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 Alberto Brambilla and Elisabetta Cinquina and Ombretta Turriziani and Francesca Falasca and Myriam Catalano and Cristina Limatola and Carlo Limatola and Est{\'e}, \{Jos{\'e} A.\} and Giovanni Maga and Romano Silvestri and Emmanuele Crespan and \{La Regina\}, Giuseppe",

year = "2020",

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

language = "English",

volume = "208",

pages = "112696--112716",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

}

Nalli, M, Armijos Rivera, JI, Masci, D, Coluccia, A, Badia, R, Riveira-Muñoz, E, Brambilla, A, Brambilla, A, Cinquina, E, Turriziani, O, Falasca, F, Catalano, M, Limatola, C, 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. 112696-112716. https://doi.org/10.1016/j.ejmech.2020.112696

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 - Brambilla, Alberto

AU - Cinquina, Elisabetta

AU - Turriziani, Ombretta

AU - Falasca, Francesca

AU - Catalano, Myriam

AU - Limatola, Cristina

AU - Limatola, Carlo

AU - Esté, José A.

AU - Maga, Giovanni

AU - Silvestri, Romano

AU - Crespan, Emmanuele

AU - La Regina, Giuseppe

PY - 2020

Y1 - 2020

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.

KW - AIDS

KW - Anti-HIV Agents

KW - Cell Line, Tumor

KW - Drug Design

KW - Drug Synergism

KW - HIV Reverse Transcriptase

KW - HIV-1

KW - Humans

KW - Indoles

KW - Indolylarylsulfone

KW - Microbial Sensitivity Tests

KW - Molecular Docking Simulation

KW - Molecular Dynamics Simulation

KW - Molecular Structure

KW - Mutation

KW - Non-nucleoside reverse transcriptase inhibitor

KW - Protein Binding

KW - Reverse Transcriptase Inhibitors

KW - Reverse transcriptase

KW - Structure-Activity Relationship

KW - Sulfones

KW - Zidovudine

KW - AIDS

KW - Anti-HIV Agents

KW - Cell Line, Tumor

KW - Drug Design

KW - Drug Synergism

KW - HIV Reverse Transcriptase

KW - HIV-1

KW - Humans

KW - Indoles

KW - Indolylarylsulfone

KW - Microbial Sensitivity Tests

KW - Molecular Docking Simulation

KW - Molecular Dynamics Simulation

KW - Molecular Structure

KW - Mutation

KW - Non-nucleoside reverse transcriptase inhibitor

KW - Protein Binding

KW - Reverse Transcriptase Inhibitors

KW - Reverse transcriptase

KW - Structure-Activity Relationship

KW - Sulfones

KW - Zidovudine

UR - http://hdl.handle.net/10807/195209

U2 - 10.1016/j.ejmech.2020.112696

DO - 10.1016/j.ejmech.2020.112696

M3 - Article

SN - 0223-5234

VL - 208

SP - 112696

EP - 112716

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

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

Abstract

UN SDGs

Keywords

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