tetano
Editor, Senior Moderator
Antiviral Res
. 2022 Dec 8;105484.
doi: 10.1016/j.antiviral.2022.105484. Online ahead of print.
Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics
Jimena Pérez-Vargas[SUP] 1 [/SUP], Tirosh Shapira[SUP] 1 [/SUP], Andrea D Olmstead[SUP] 1 [/SUP], Ivan Villanueva[SUP] 1 [/SUP], Connor A H Thompson[SUP] 1 [/SUP], Siobhan Ennis[SUP] 2 [/SUP], Guang Gao[SUP] 3 [/SUP], Joshua DeGuzman[SUP] 1 [/SUP], David E Williams[SUP] 4 [/SUP], Meng Wang[SUP] 4 [/SUP], Aaleigha Chin[SUP] 1 [/SUP], Diana Bautista-Sánchez[SUP] 1 [/SUP], Olga Agafitei[SUP] 2 [/SUP], Paul Levett[SUP] 5 [/SUP], Xuping Xie[SUP] 6 [/SUP], Genoveffa Nuzzo[SUP] 7 [/SUP], Vitor F Freire[SUP] 8 [/SUP], Jairo I Quintana-Bulla[SUP] 8 [/SUP], Darlon I Bernardi[SUP] 8 [/SUP], Juliana R Gubiani[SUP] 8 [/SUP], Virayu Suthiphasilp[SUP] 9 [/SUP], Achara Raksat[SUP] 9 [/SUP], Pornphimol Meesakul[SUP] 9 [/SUP], Isaraporn Polbuppha[SUP] 9 [/SUP], Sarot Cheenpracha[SUP] 10 [/SUP], Wuttichai Jaidee[SUP] 11 [/SUP], Kwanjai Kanokmedhakul[SUP] 12 [/SUP], Chavi Yenjai[SUP] 12 [/SUP], Boonyanoot Chaiyosang[SUP] 12 [/SUP], Helder Lopes Teles[SUP] 13 [/SUP], Emiliano Manzo[SUP] 7 [/SUP], Angelo Fontana[SUP] 14 [/SUP], Richard Leduc[SUP] 15 [/SUP], Pierre-Luc Boudreault[SUP] 15 [/SUP], Roberto G S Berlinck[SUP] 8 [/SUP], Surat Laphookhieo[SUP] 9 [/SUP], Somdej Kanokmedhakul[SUP] 12 [/SUP], Ian Tietjen[SUP] 16 [/SUP], Artem Cherkasov[SUP] 17 [/SUP], Mel Krajden[SUP] 18 [/SUP], Ivan Robert Nabi[SUP] 19 [/SUP], Masahiro Niikura[SUP] 2 [/SUP], Pei-Yong Shi[SUP] 6 [/SUP], Raymond J Andersen[SUP] 20 [/SUP], François Jean[SUP] 21 [/SUP]
Affiliations
Abstract
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 (EC[SUB]50[/SUB]) below 50 μM against mNG-SARS-CoV-2; 16 of these had EC[SUB]50[/SUB] values below 10 μM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC[SUB]50[/SUB] 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.
Keywords: Host-directed antiviral; Human TMPRSS2; Human V-ATPase; Human protein kinase C; SARS-CoV-2 variants of concern.
. 2022 Dec 8;105484.
doi: 10.1016/j.antiviral.2022.105484. Online ahead of print.
Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics
Jimena Pérez-Vargas[SUP] 1 [/SUP], Tirosh Shapira[SUP] 1 [/SUP], Andrea D Olmstead[SUP] 1 [/SUP], Ivan Villanueva[SUP] 1 [/SUP], Connor A H Thompson[SUP] 1 [/SUP], Siobhan Ennis[SUP] 2 [/SUP], Guang Gao[SUP] 3 [/SUP], Joshua DeGuzman[SUP] 1 [/SUP], David E Williams[SUP] 4 [/SUP], Meng Wang[SUP] 4 [/SUP], Aaleigha Chin[SUP] 1 [/SUP], Diana Bautista-Sánchez[SUP] 1 [/SUP], Olga Agafitei[SUP] 2 [/SUP], Paul Levett[SUP] 5 [/SUP], Xuping Xie[SUP] 6 [/SUP], Genoveffa Nuzzo[SUP] 7 [/SUP], Vitor F Freire[SUP] 8 [/SUP], Jairo I Quintana-Bulla[SUP] 8 [/SUP], Darlon I Bernardi[SUP] 8 [/SUP], Juliana R Gubiani[SUP] 8 [/SUP], Virayu Suthiphasilp[SUP] 9 [/SUP], Achara Raksat[SUP] 9 [/SUP], Pornphimol Meesakul[SUP] 9 [/SUP], Isaraporn Polbuppha[SUP] 9 [/SUP], Sarot Cheenpracha[SUP] 10 [/SUP], Wuttichai Jaidee[SUP] 11 [/SUP], Kwanjai Kanokmedhakul[SUP] 12 [/SUP], Chavi Yenjai[SUP] 12 [/SUP], Boonyanoot Chaiyosang[SUP] 12 [/SUP], Helder Lopes Teles[SUP] 13 [/SUP], Emiliano Manzo[SUP] 7 [/SUP], Angelo Fontana[SUP] 14 [/SUP], Richard Leduc[SUP] 15 [/SUP], Pierre-Luc Boudreault[SUP] 15 [/SUP], Roberto G S Berlinck[SUP] 8 [/SUP], Surat Laphookhieo[SUP] 9 [/SUP], Somdej Kanokmedhakul[SUP] 12 [/SUP], Ian Tietjen[SUP] 16 [/SUP], Artem Cherkasov[SUP] 17 [/SUP], Mel Krajden[SUP] 18 [/SUP], Ivan Robert Nabi[SUP] 19 [/SUP], Masahiro Niikura[SUP] 2 [/SUP], Pei-Yong Shi[SUP] 6 [/SUP], Raymond J Andersen[SUP] 20 [/SUP], François Jean[SUP] 21 [/SUP]
Affiliations
- PMID: 36503013
- DOI: 10.1016/j.antiviral.2022.105484
Abstract
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 (EC[SUB]50[/SUB]) below 50 μM against mNG-SARS-CoV-2; 16 of these had EC[SUB]50[/SUB] values below 10 μM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC[SUB]50[/SUB] 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.
Keywords: Host-directed antiviral; Human TMPRSS2; Human V-ATPase; Human protein kinase C; SARS-CoV-2 variants of concern.