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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.

SUBMITTER: Perez-Vargas J

PROVIDER: S-EPMC9729583 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Pérez-Vargas Jimena J Shapira Tirosh T Olmstead Andrea D AD Villanueva Ivan I Thompson Connor A H CAH Ennis Siobhan S Gao Guang G De Guzman Joshua J Williams David E DE Wang Meng M Chin Aaleigha A Bautista-Sánchez Diana D Agafitei Olga O Levett Paul P Xie Xuping X Nuzzo Genoveffa G Freire Vitor F VF Quintana-Bulla Jairo I JI Bernardi Darlon I DI Gubiani Juliana R JR Suthiphasilp Virayu V Raksat Achara A Meesakul Pornphimol P Polbuppha Isaraporn I Cheenpracha Sarot S Jaidee Wuttichai W Kanokmedhakul Kwanjai K Yenjai Chavi C Chaiyosang Boonyanoot B Teles Helder Lopes HL Manzo Emiliano E Fontana Angelo A Leduc Richard R Boudreault Pierre-Luc PL Berlinck Roberto G S RGS Laphookhieo Surat S Kanokmedhakul Somdej S Tietjen Ian I Cherkasov Artem A Krajden Mel M Nabi Ivan Robert IR Niikura Masahiro M Shi Pei-Yong PY Andersen Raymond J RJ Jean François F

Antiviral research 20221208

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 ...[more]

PMID: 36503013

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Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), known to cause the disease COVID-19, was declared a pandemic in early 2020. The objective of this review was to collate information regarding the potential of plants and natural products to inhibit coronavirus and targets associated with infection in humans and to highlight known drugs, which may have potential activity against SARS-CoV-2. Due to the similarity in the RNA genome, main proteases, and primary host receptor between SARS-CoV and SARS-CoV-2, a review was conducted on plants and secondary metabolites, which have shown activity against SARS-CoV. Numerous scientific reports on the potential of plants and secondary metabolites against SARS-CoV infection were found, providing important information on their possible activity against SARS-CoV-2. Based on current literature, 83 compounds have been identified with the potential to inhibit COVID-19. The most prominent selectivity was found for the alkaloid, lycorine, the lignan, savinin, and the abietane terpenoid, 8-beta-hydroxyabieta-9(11),13-dien-12-one with selectivity index values greater than 945, 667, and 510, respectively. Plants and their secondary metabolites, with activity against targets associated with the SARS-CoV infection, could provide valuable leads for the development into drugs for the novel SARS-CoV-2. The prospects of using computational methods to screen secondary metabolites against SARS-CoV targets are briefly discussed, and the drawbacks have been highlighted. Finally, we discuss plants traditionally used in Southern Africa for symptoms associated with respiratory viral infections and influenza, such as coughs, fever, and colds. However, only a few of these plants have been screened against SARS-CoV. Natural products hold a prominent role in discovering novel therapeutics to mitigate the current COVID-19 pandemic; however, further investigations regarding in vitro, in vivo, pre-clinical, and clinical phases are still required.

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

Publications

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

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