Stand Up to Stand Out: Natural Dietary Polyphenols Curcumin, Resveratrol, and Gossypol as Potential Therapeutic Candidates against Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Abstract

The COVID-19 pandemic has stimulated collaborative drug discovery efforts in academia and the industry with the aim of developing therapies and vaccines that target SARS-CoV-2. Several novel therapies have been approved and deployed in the last three years. However, their clinical application has revealed limitations due to the rapid emergence of viral variants. Therefore, the development of next-generation SARS-CoV-2 therapeutic agents with a high potency and safety profile remains a high priority for global health. Increasing awareness of the "back to nature" approach for improving human health has prompted renewed interest in natural products, especially dietary polyphenols, as an additional therapeutic strategy to treat SARS-CoV-2 patients, owing to its good safety profile, exceptional nutritional value, health-promoting benefits (including potential antiviral properties), affordability, and availability. Herein, we describe the biological properties and pleiotropic molecular mechanisms of dietary polyphenols curcumin, resveratrol, and gossypol as inhibitors against SARS-CoV-2 and its variants as observed in in vitro and in vivo studies. Based on the advantages and disadvantages of dietary polyphenols and to obtain maximal benefits, several strategies such as nanotechnology (e.g., curcumin-incorporated nanofibrous membranes with antibacterial-antiviral ability), lead optimization (e.g., a methylated analog of curcumin), combination therapies (e.g., a specific combination of plant extracts and micronutrients), and broad-spectrum activities (e.g., gossypol broadly inhibits coronaviruses) have also been emphasized as positive factors in the facilitation of anti-SARS-CoV-2 drug development to support effective long-term pandemic management and control.

Keywords: COVID-19; SARS-CoV-2; broad-spectrum activities; combination therapies; curcumin; gossypol; lead optimization; nanotechnology; natural dietary polyphenols; resveratrol.

Figure 2

Curcumin, a turmeric-derived complementary drug, may be effective against COVID-19 with the assistance of combination therapies, nanotechnology, and lead optimization. (a) The chemical structure of curcumin isolated from Curcuma longa L. (b) Clinical trials of curcumin in the form of oral co-supplementation and throat spray. (c) Schematic representation of the CUR-PS-NP preparation process and its use in preventing lung and liver injuries associated with SARS-CoV-2 spike protein-mediated cytokine storms. (Adapted with permission from TOC and Figure 2 of Sharma et al.; ACS Appl. Bio Mater. 2022, 5, 483–491 [57]. Copyright © 2022 American Chemical Society). (d) The process involved in the preparation of curcumin-incorporated nanofibrous membranes (A–A mask) and a schematic representation of the SARS-CoV-2 inactivation mechanism. (Adapted with permission [56]. Copyright © 2022 Elsevier B.V.) (e) Curcumin-based lead optimization.

Figure 1

The chemical structures of curcumin, resveratrol, and gossypol. Gossypol exists as enantiomers due to the restricted rotation around the internal binaphthyl bond.

Figure 3

Chemical structure of resveratrol and its natural derivatives. Chemical structure of resveratrol, which can be isolated from several dietary sources such as grapes, peanuts, pistachios, blueberries, etc.; Chemical structures of piceatannol (hydroxylated analog) and pterostilbene (methoxylated analog); Chemical structures of trans-ε-viniferin (dimer), miyabenol C (trimer), and hopeaphenol (tetramer), vatalbinoside A (tetramer), vaticanol B (tetramer), and kobophenol A (tetramer).

Figure 4

Possible mechanism of action of resveratrol and its derivatives for SARS-CoV-2 treatment. (a) Possible mechanism of action of resveratrol and its derivatives in the treatment of SARS-CoV-2 involving the inhibition of RBD/ACE2 binding. (b) A model showing how SARS-CoV-2 ORF3a impairs autophagosome maturation by disrupting the HOPS-mediated assembly of the SNARE complex. (Adapted with permission [75]. Copyright © 2020 Elsevier B.V.) (c) Resveratrol inhibits SARS-CoV-2 ORF3a. ORF3a, an essential contributor to infection and propagation of SARS-CoV-2, is a potential therapeutic target against COVID-19.

Figure 5

The chemical structures of gossypol and acetate gossypol.

Figure 6

Schematic illustration of two gossypol (GOS) molecules acting as SARS-CoV-2 inhibitors via blocking the highly conserved RNA-dependent RNA polymerase. GOS inhibits RdRp activity by occupying the binding site for the RNA template [(−)-GOS, named GOS1] and primer [(+)-GOS, named GOS2]), consequentially inhibiting the catalytic activity of RdRp [24].