Natural Products with Tandem Anti-inflammatory, Immunomodulatory and Anti-SARS-CoV/2 Effects: A Drug Discovery Perspective against SARS-CoV-2

Abstract

Background: COVID-19 is still causing victims with long-term health consequences, mass deaths, and collapsing healthcare systems around the world. The disease has no efficient drugs. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CLpro) and papain-like protease (PLpro) sequences, respectively. This resemblance could be significant in the search for drug candidates with antiviral effects against SARS-CoV-2. Objective: This paper is a compilation of natural products that inhibit SARS-CoV 3CLpro and PLpro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CLpro and PLpro as targets to propose a list of hit compounds. Method: The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages. Results: Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed in previous studies immunomodulatory effects. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PLpro and 3CLpro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature. Conclusion: This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidate for the search of antibiotics against COVID-19.

Studies of Cytotoxicity Effects, SARS‐CoV‐2 Main Protease Inhibition, and in Silico Interactions of Synthetic Chalcones

“…Chalcone‐derived compounds have attracted much interest not only for their simple synthesis but also for their broad pharmacological properties. As reported in previous studies, synthetic chalcones showed promising inhibitory effects against cruzain, a cysteine protease of Trypanosoma cruzi [8] . Natural alkylated chalcones namely isobavachalcone, 4‐hydroxyderricin, xanthoangelol, xanthoangelol F, xanthoangelol D, xanthoangelol E, xanthoangelol B, xanthoangelol G, and xanthokeistal A showed strong to moderate inhibition of SARS‐CoV 3CL pro by impairing its cis‐ cleavage activity [7,9] .…”

“…Among the studied compounds, chalcones represent one of the most investigated for the inhibition of cysteine proteases. It is a naturally occurring family that contains a scaffold of 1,3‐diaryl‐2‐propen‐1‐one [7,8] . Chalcone‐derived compounds have attracted much interest not only for their simple synthesis but also for their broad pharmacological properties.…”

The exploration of phytocompounds theoretically combats SARS-CoV-2 pandemic against virus entry, viral replication and immune evasion

“…Furthermore, four HCV protease inhibitor drugs, Simeprevir, Vaniprevir, Paritaprevir, and Grazoprevir with remdesivir inhibit the SARS CoV-2 PL pro [81] . One study showed that Amentoflavone, Rubranoside B, Savinin, Psoralidin, Hirsutenone, and Papyriflavonol A are good drug candidate for the search of antibiotics against PL pro and M pro [82] . Nine natural biflavones were also confirmed to be effective PL pro inhibitors with IC50 values ranging from 9.5 to 43.2 μM via anti-proteolytic activity determination [83] …”

Small molecules in the treatment of COVID-19

“…Besides the above common flavones, amentoflavone, a hydroxyflavone and bioflavonoid, also has shown binding affinity with M pro , RdRp, NSP13, NSP15, and ACE2 in several in silico surveys. 349 – 351 Similar to flavanols, the hydroxy groups of flavones can be glycosylated, thus forming flavone glycosides. Baicalin, a 7-O-glucuronide of baicalein, is a biologically active flavonoid of natural origin obtained primarily from the roots of Scutellaria baicalensis Georgi.…”