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

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

  • Eur J Med Chem. 2020 Dec 15;208:112696. doi: 10.1016/j.ejmech.2020.112696.
Marianna Nalli 1,  Jorge I Armijos Rivera 2,  Domiziana Masci 1,  Antonio Coluccia 1,  Roger Badia 3,  Eva Riveira-Muñoz 4,  Alessandro Brambilla 5,  Elisabetta Cinquina 6,  Ombretta Turriziani 6,  Francesca Falasca 6,  Myriam Catalano 7,  Cristina Limatola 7,  José A Esté 4,  Giovanni Maga 5,  Romano Silvestri 8,  Emmanuele Crespan 9,  Giuseppe La Regina 10
Affiliations

Affiliations

  • 1 Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie Del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Rome, Italy.
  • 2 Laboartorio de Enzimologia Patologica e Inhibidores Enzimaticos, Universidad Nacional de Loja, Avenida Reinaldo Espinoza S/N - Ciudad Universitaria Guillermo Falconí, Loja, Ecuador; Institute of Molecular Genetics IGM-CNR, National Research Council, Via Abbiategrasso 207, 27100, Pavia, Italy.
  • 3 AIDS Research Institute - IrsiCaixa, Hospitals Germans Trias I Pujol, Universitat Autonóma de Barcelona, 08916, Badalona, Spain; Health Research Institute Germans Trias I Pujol (IGTP), Hospital Germans Trias I Pujol, Universitat Autonóma de Barcelona, 08916, Badalona, Spain.
  • 4 AIDS Research Institute - IrsiCaixa, Hospitals Germans Trias I Pujol, Universitat Autonóma de Barcelona, 08916, Badalona, Spain.
  • 5 Institute of Molecular Genetics IGM-CNR, National Research Council, Via Abbiategrasso 207, 27100, Pavia, Italy.
  • 6 Dipartimento di Medicina Molecolare, Sapienza Università di Roma, Viale Regina Elena 291, 00161, Rome, Italy.
  • 7 Dipartimento di Fisiologia e Farmacologia "Vittorio Erspamer", Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Rome, Italy; IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, Italy.
  • 8 Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie Del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Rome, Italy. Electronic address: [email protected].
  • 9 Institute of Molecular Genetics IGM-CNR, National Research Council, Via Abbiategrasso 207, 27100, Pavia, Italy. Electronic address: [email protected].
  • 10 Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie Del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Rome, Italy. Electronic address: [email protected].
PMID: 32883642 DOI: 10.1016/j.ejmech.2020.112696
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; HIV-1; Indolylarylsulfone; Non-nucleoside reverse transcriptase inhibitor; Reverse transcriptase.

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