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

The urgent need for new classes of orally available, safe, and effective antivirals─covering a breadth of emerging viruses─is evidenced by the loss of life and economic challenges created by the HIV-1 and SARS-CoV-2 pandemics. As frontline interventions, small-molecule antivirals can be deployed prophylactically or postinfection to control the initial spread of outbreaks by reducing transmissibility and symptom severity. Natural products have an impressive track record of success as prototypic antivirals and continue to provide new drugs through synthesis, medicinal chemistry, and optimization decades after discovery. Here, we demonstrate an approach using computational analysis typically used for rational drug design to identify and develop natural product-inspired antivirals. This was done with the goal of identifying natural product prototypes to aid the effort of progressing toward safe, effective, and affordable broad-spectrum inhibitors of Betacoronavirus replication by targeting the highly conserved RNA 2'-O-methyltransferase (2'-O-MTase). Machaeriols RS-1 (7) and RS-2 (8) were identified using a previously outlined informatics approach to first screen for natural product prototypes, followed by in silico-guided synthesis. Both molecules are based on a rare natural product group. The machaeriols (3-6), isolated from the genus Machaerium, endemic to Amazonia, inhibited the SARS-CoV-2 2'-O-MTase more potently than the positive control, Sinefungin (2), and in silico modeling suggests distinct molecular interactions. This report highlights the potential of computationally driven screening to leverage natural product libraries and improve the efficiency of isolation or synthetic analog development.

Non-enzymatic glycoxidation linked with nutrition enhances the tumorigenic capacity of prostate cancer epithelia through AGE mediated activation of RAGE in cancer associated fibroblasts.

The molecular implications of food consumption on cancer etiology are poorly defined. The rate of nutrition associated non-enzymatic glycoxidation, a reaction that occurs between reactive carbonyl groups on linear sugars and nucleophilic amino, lysyl and arginyl groups on fats and proteins, is rapidly increased by food cooking and manufacturing processes. In this study, we assign nutrition-associated glycoxidation with significant oncogenic potential, promoting prostate tumor growth, progression, and metastasis in vivo. Advanced glycation end products (AGEs) are the final irreversible product of non-enzymatic glycoxidation. Exogenous treatment of prostate tumor cells with a single AGE peptide replicated glycoxidation induced tumor growth in vivo. Mechanistically, receptor for AGE (RAGE) deficiency in the stroma inhibited AGE mediated tumor growth. Functionally, AGE treatment induced RAGE dimerization in activated fibroblasts which sustained and increased the migratory potential of tumor epithelial cells. These data identify a novel nutrition associated pathway that can promote a tissue microenvironment conducive for aggressive tumor growth. Targeted and/or interventional strategies aimed at reducing AGE bioavailability as a consequence of nutrition may be viewed as novel chemoprevention initiatives.

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

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.