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. Gubiani; Virayu 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

doi:10.1016/j.antiviral.2022.105484

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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 (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 language	English (US)
Article number	105484
Journal	Antiviral research
Volume	209
DOIs	https://doi.org/10.1016/j.antiviral.2022.105484
State	Published - Jan 2023

Keywords

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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10.1016/j.antiviral.2022.105484

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Pérez-Vargas, J., Shapira, T., Olmstead, A. D., Villanueva, I., Thompson, C. A. H., Ennis, S., Gao, G., De Guzman, J., Williams, D. E., Wang, M., Chin, A., Bautista-Sánchez, D., Agafitei, O., Levett, P., Xie, X., Nuzzo, G., Freire, V. F., Quintana-Bulla, J. I., Bernardi, D. I., ... Jean, F. (2023). Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics. Antiviral research, 209, Article 105484. https://doi.org/10.1016/j.antiviral.2022.105484

Pérez-Vargas, J, Shapira, T, Olmstead, AD, Villanueva, I, Thompson, CAH, Ennis, S, Gao, G, De Guzman, J, Williams, DE, Wang, M, Chin, A, Bautista-Sánchez, D, Agafitei, O, Levett, P, Xie, X, Nuzzo, G, Freire, VF, Quintana-Bulla, JI, Bernardi, DI, Gubiani, JR, Suthiphasilp, V, Raksat, A, Meesakul, P, Polbuppha, I, Cheenpracha, S, Jaidee, W, Kanokmedhakul, K, Yenjai, C, Chaiyosang, B, Teles, HL, Manzo, E, Fontana, A, Leduc, R, Boudreault, PL, Berlinck, RGS, Laphookhieo, S, Kanokmedhakul, S, Tietjen, I, Cherkasov, A, Krajden, M, Nabi, IR, Niikura, M, Shi, P-Y, Andersen, RJ & Jean, F 2023, 'Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics', Antiviral research, vol. 209, 105484. https://doi.org/10.1016/j.antiviral.2022.105484

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title = "Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics",

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 (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.",

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

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2023",

month = jan,

doi = "10.1016/j.antiviral.2022.105484",

language = "English (US)",

volume = "209",

journal = "Antiviral research",

issn = "0166-3542",

publisher = "Elsevier",

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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

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

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