TY - JOUR
T1 - Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics
AU - Pérez-Vargas, Jimena
AU - Shapira, Tirosh
AU - Olmstead, Andrea D.
AU - Villanueva, Ivan
AU - Thompson, Connor A.H.
AU - Ennis, Siobhan
AU - Gao, Guang
AU - De Guzman, Joshua
AU - Williams, David E.
AU - Wang, Meng
AU - Chin, Aaleigha
AU - Bautista-Sánchez, Diana
AU - Agafitei, Olga
AU - Levett, Paul
AU - Xie, Xuping
AU - Nuzzo, Genoveffa
AU - Freire, Vitor F.
AU - Quintana-Bulla, Jairo I.
AU - Bernardi, Darlon I.
AU - Gubiani, Juliana R.
AU - Suthiphasilp, Virayu
AU - Raksat, Achara
AU - Meesakul, Pornphimol
AU - Polbuppha, Isaraporn
AU - Cheenpracha, Sarot
AU - Jaidee, Wuttichai
AU - Kanokmedhakul, Kwanjai
AU - Yenjai, Chavi
AU - Chaiyosang, Boonyanoot
AU - Teles, Helder Lopes
AU - Manzo, Emiliano
AU - Fontana, Angelo
AU - Leduc, Richard
AU - Boudreault, Pierre Luc
AU - Berlinck, Roberto G.S.
AU - Laphookhieo, Surat
AU - Kanokmedhakul, Somdej
AU - Tietjen, Ian
AU - Cherkasov, Artem
AU - Krajden, Mel
AU - Nabi, Ivan Robert
AU - Niikura, Masahiro
AU - Shi, Pei Yong
AU - Andersen, Raymond J.
AU - Jean, François
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Host-directed antiviral
KW - Human TMPRSS2
KW - Human V-ATPase
KW - Human protein kinase C
KW - SARS-CoV-2 variants of concern
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U2 - 10.1016/j.antiviral.2022.105484
DO - 10.1016/j.antiviral.2022.105484
M3 - Article
C2 - 36503013
AN - SCOPUS:85144436100
SN - 0166-3542
VL - 209
JO - Antiviral research
JF - Antiviral research
M1 - 105484
ER -