Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication
Abhishek Asthana,
Angela Corona,
Woo-Jin Shin,
Mi-Jeong Kwak,
Christina Gaughan,
Enzo Tramontano,
Jae U. Jung,
Rainer Schobert,
Babal Kant Jha,
Robert H. Silverman,
Bernhard Biersack
Affiliations
Abhishek Asthana
Cancer Biology, Lerner Research Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44106, USA
Angela Corona
Laboratorio di Virologia Molecolare, Dipartimento di Scienze della Vita e Dell’Ambiente, Universitá degli Studi di Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato, Italy
Woo-Jin Shin
Cancer Biology, Lerner Research Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44106, USA
Mi-Jeong Kwak
Cancer Biology, Lerner Research Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44106, USA
Christina Gaughan
Cancer Biology, Lerner Research Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44106, USA
Enzo Tramontano
Laboratorio di Virologia Molecolare, Dipartimento di Scienze della Vita e Dell’Ambiente, Universitá degli Studi di Cagliari, Cittadella Universitaria di Monserrato SS554, 09042 Monserrato, Italy
Jae U. Jung
Cancer Biology, Lerner Research Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44106, USA
Rainer Schobert
Organic Chemistry 1, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany
Babal Kant Jha
Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute and Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44195, USA
Robert H. Silverman
Cancer Biology, Lerner Research Institute, Cleveland Clinic, 2111 East 96th St, Cleveland, OH 44106, USA
Bernhard Biersack
Organic Chemistry 1, University of Bayreuth, Universitätsstrasse 30, 95440 Bayreuth, Germany
Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3′-to-5′ exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.
