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
  • 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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