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

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

Research output: Contribution to journalArticlepeer-review


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 μM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 μM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated 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.

Original languageEnglish (US)
Article number105484
JournalAntiviral research
StatePublished - Jan 2023


  • Host-directed antiviral
  • Human TMPRSS2
  • Human V-ATPase
  • Human protein kinase C
  • SARS-CoV-2 variants of concern

ASJC Scopus subject areas

  • Pharmacology
  • Virology


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