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.

In-Silico Approaches for the Screening and Discovery of Broad-Spectrum Marine Natural Product Antiviral Agents Against Coronaviruses

“…This type of high throughput workflow allows for the rapid creation of natural, antiviral drug leads and could effectively lead to a broad-spectrum prophylactic/therapeutic for future betacoronavirus pathogens. 46 …”

Manzamine-A Alters In Vitro Calvarial Osteoblast Function

“…Marine natural products remain a highly important source for emerging drugs, especially in the treatments of cancers and viral infections [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. One such potential drug is manzamine-A, a marine sponge derived alkaloid that emerged in the field of infectious disease as a promising control for malaria [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. The understanding of manzamine and derived analogs utility in medicine is nascent, but is proposed to include treatment for malaria [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ], herpes [ 29 , 36 , 37 , 38 ], HIV [ 29 , 32 , 39 , 40 , 41 , 42 , 43 , 44 ], cancer [ 6 , 10 , 13 , 35 , 37 , 38 , 39 , 44 , 45 ], as well as generally having anti-bacterial, antifungal, and anti-inflammatory activities [ 15 , 17 , 19...…”

Informatics and Computational Approaches for the Discovery and Optimization of Natural Product-Inspired Inhibitors of the SARS-CoV-2 2′-O-Methyltransferase

“…The present approach drew upon the highly conserved nature of the SARS-CoV-2, SARS, and MERS S-adenosylmethionine (SAM) (1)-dependent 2′-O-MTase protein as the therapeutic target. 25,26 The 2′-O-MTase with EC no. 2.1.1.57 (https://www.brenda-enzymes.org/enzyme.php?ecno=2.1.1.…”

“…8−10,33−36 Presented here is a continuation of previous work described in the viewpoint "Contemporary Approaches to the Discovery and Development of Broad-Spectrum Natural Product Prototypes for the Control of Coronaviruses". 25 The intent of that earlier work was to describe strategies for efficiently identifying natural products using in silico molecular modeling techniques typically used in rational drug design with synthetic molecule libraries. 37 This effort was also intended to address production limitations commonly encountered in natural product screening where access to source material and the labor of isolating large sets of compounds can quickly outstrip an academic laboratory's research capacity.…”

“…The present approach drew upon the highly conserved nature of the SARS-CoV-2, SARS, and MERS S -adenosylmethionine (SAM) ( 1 )-dependent 2′-O-MTase protein as the therapeutic target. , The 2′-O-MTase with EC no. 2.1.1.57 () is present in many organisms and most notably as a therapeutic target for the +ssRNA viruses such as coronaviruses and Zika and Dengue viruses .…”