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Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses.

ABSTRACT: The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense of extraction, purification, and screening in BioSafety Laboratories (BSL)3 laboratories. The unparalleled structural diversity and complexity of NPs is an extraordinary resource for the discovery and development of broad-spectrum inhibitors of viral genera, including Betacoronavirus, which contains MERS, SARS, SARS-CoV-2, and the common cold. There are two key technological advances that have created unique opportunities for the identification of NP prototypes with greater efficiency: (1) the application of structural databases for NPs and target proteins and (2) the application of modern MS techniques to assess protein-ligand interactions directly from NP extracts. These approaches, developed over years, now allow for the identification and isolation of unique antiviral ligands without the immediate need for BSL3 facilities. Overall, the goal is to improve the success rate of NP-based screening by focusing resources on source materials with a higher likelihood of success, while simultaneously providing opportunities for the discovery of novel ligands to selectively target proteins involved in viral infection.

SUBMITTER: Hanna GS

PROVIDER: S-EPMC8547502 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses.

Hanna George S GS Choo Yeun-Mun YM Harbit Ryan R Paeth Heather H Wilde Sarah S Mackle James J Verga Jacopo-Umberto JU Wolf Bethany J BJ Thomas Olivier P OP Croot Peter P Cray James J Thomas Courtney C Li Ling-Zhi LZ Hardiman Gary G Hu Jin-Feng JF Wang Xiaojuan X Patel Dharmeshkumar D Schinazi Raymond F RF O'Keefe Barry R BR Hamann Mark T MT

Journal of natural products 20211022 11

The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense ...[more]

PMID: 34677966

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Project description:Over the past 20 years, the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2 emerged, causing severe human respiratory diseases throughout the globe. Developing broad-spectrum drugs would be invaluable in responding to new, emerging coronaviruses and to address unmet urgent clinical needs. Main protease (Mpro; also known as 3CLpro) has a major role in the coronavirus life cycle and is one of the most important targets for anti-coronavirus agents. We show that a natural product, noncovalent inhibitor, shikonin, is a pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, human coronavirus (HCoV)-HKU1, HCoV-NL63, and HCoV-229E with micromolar half maximal inhibitory concentration (IC50) values. Structures of the main protease of different coronavirus genus, SARS-CoV from the betacoronavirus genus and HCoV-NL63 from the alphacoronavirus genus, were determined by X-ray crystallography and revealed that the inhibitor interacts with key active site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses as well as emerging coronaviruses of the future. Given the importance of the main protease for coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents. IMPORTANCE The current pandemic has created an urgent need for broad-spectrum inhibitors of SARS-CoV-2. The main protease is relatively conservative compared to the spike protein and, thus, is one of the most promising targets in developing anti-coronavirus agents. We solved the crystal structures of the main protease of SARS-CoV and HCoV-NL63 that bound to shikonin. The structures provide important insights, have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad-spectrum anti-coronavirus ligands as new therapeutic agents.

Project description:BackgroundFungi are the second most abundant type of human pathogens. Invasive fungal pathogens are leading causes of life-threatening infections in clinical settings. Toxicity to the host and drug-resistance are two major deleterious issues associated with existing antifungal agents. Increasing a host's tolerance and/or immunity to fungal pathogens has potential to alleviate these problems. A host's tolerance may be improved by modulating the immune system such that it responds more rapidly and robustly in all facets, ranging from the recognition of pathogens to their clearance from the host. An understanding of biological processes and genes that are perturbed during attempted fungal exposure, colonization, and/or invasion will help guide the identification of endogenous immunomodulators and/or small molecules that activate host-immune responses such as specialized adjuvants.ResultsIn this study, we present computational techniques and approaches using publicly available transcriptional data sets, to predict immunomodulators that may act against multiple fungal pathogens. Our study analyzed data sets derived from host cells exposed to five fungal pathogens, namely, Alternaria alternata, Aspergillus fumigatus, Candida albicans, Pneumocystis jirovecii, and Stachybotrys chartarum. We observed statistically significant associations between host responses to A. fumigatus and C. albicans. Our analysis identified biological processes that were consistently perturbed by these two pathogens. These processes contained both immune response-inducing genes such as MALT1, SERPINE1, ICAM1, and IL8, and immune response-repressing genes such as DUSP8, DUSP6, and SPRED2. We hypothesize that these genes belong to a pool of common immunomodulators that can potentially be activated or suppressed (agonized or antagonized) in order to render the host more tolerant to infections caused by A. fumigatus and C. albicans.ConclusionsOur computational approaches and methodologies described here can now be applied to newly generated or expanded data sets for further elucidation of additional drug targets. Moreover, identified immunomodulators may be used to generate experimentally testable hypotheses that could help in the discovery of broad-spectrum immunotherapeutic interventions. All of our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/~murali/supplements/2013-kidane-bmc.

Dataset Information

Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses.

Publications

Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses.

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