Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics

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Perez-Vargas, Jimena ; Shapira, Tirosh ; Olmstead, Andrea D. ; Villanueva, Ivan ; Thompson, Connor A. H. ; Ennis, Siobhan ; Gao, Guang ; De Guzman, Joshua ; Williams, David E. ; Wang, Meng ; Chin, Aaleigha ; Bautista-Sanchez, Diana ; Agafitei, Olga ; Levett, Paul ; Xie, Xuping ; Nuzzo, Genoveffa ; Freire, Vitor F. ; Quintana-Bulla, Jairo I. ; Bernardi, Darlon I. ; Gubiani, Juliana R. ; Suthiphasilp, Virayu ; Raksat, Achara ; Meesakul, Pornphimol ; Polbuppha, Isaraporn ; Cheenpracha, Sarot ; Jaideej, Wuttichai ; Kanokmedhakul, Kwanjai ; Yenjai, Chavi ; Chaiyosang, Boonyanoot ; Teles, Helder Lopes ; Manzo, Emiliano ; Fontana, Angelo ; Leducn, Richard ; Boudreault, Pierre-Luc ; Berlinck, Roberto G. S. ; Laphookhieo, Surat ; Kanokmedhakul, Somdej ; Tietjen, Ian ; Cherkasov, Artem ; Krajden, Mel ; Nabi, Ivan Robert ; Niikura, Masahiro ; Shi, Pei-Yong ; Andersen, Raymond J. ; Jean, Francois

• Tipo de documento: Artigo Científico
• Fonte: Antiviral Research; v. 209, p. 13-pg., 2022-12-20.

Resumo

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 mu M against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 mu M and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demon-strated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants. (AU)

• Processo FAPESP: 19/17721-9 - A função da Química na adaptação de holobiontes
• Beneficiário: Roberto Gomes de Souza Berlinck
• Modalidade de apoio: Auxílio à Pesquisa - Temático