Promising Natural Products for Treating SARS-CoV-2 Infection

Promising Natural Products for Treating SARS-CoV-2 Infection

Article from Cayman 2021-07-27

Due to their large therapeutic window and broad-spectrum antiviral, immunomodulatory, anti-inflammatory, and antioxidant activities, natural products derived from plants or microbes and natural product-inspired small molecules have attracted considerable attention as potential agents to combat SARS-CoV-2, the causative agent of COVID-19. These compounds offer structural diversity that can serve as molecular frameworks for inspiring novel drug discovery.

 In fact, the anti-SARS-CoV-2 compounds that garnered the most interest early on in the pandemic included ivermectin, the semisynthetic 22,23-dihydro derivative of the natural product avermectin B1 (B1a and B1b), which is produced by Streptomyces avermitilis, remdesivir, which began with structural modification of tubercidin (an antibiotic and adenosine analog that is isolated from Streptomyces tubercidicus), and EIDD-2801, which began with structurally modifying the broad-spectrum antiviral agent EIDD-1931 (N4-hydroxycytidine), which was in turn derived from the essential natural product uridine found in human plasma [1]. Read on to learn more about natural products that have potential as anti-coronavirus therapies.

Strategies to control SARS-CoV-2 infection include modulating the host immune system, blocking virus entry into host cells by interfering with the spike glycoprotein binding to the host cell membrane receptor angiotensin-converting enzyme 2 (ACE2), preventing the synthesis of viral RNA by acting on the genetic material of the virus, inhibiting viral replication by acting on enzymes critical to the virus (e.g., RNA-dependent RNA polymerase (RdRp), the main protease (Mpro), also known as the chymotrypsin-like protease (3CLpro), or the papain-like protease (PLpro)), or inhibiting the virus's self-assembly process through acting on some structural proteins like the nucleocapsid protein. Molecular docking analysis of various natural products in complex with several of these key target proteins has revealed multiple promising candidates with excellent binding affinity.

Spike and ACE2

The SARS-CoV-2 spike protein located on the outer envelope of the virion is synthesized as a precursor protein. Its cleavage by host cell proteases (i.e., transmembrane protease serine 2 (TMPRSS2), endosomal cathepsin L protease, and/or human airway trypsin-like protease) is an essential step for virus fusion to the ACE2 receptor on the host cell membrane. Withaferin A, a steroidal lactone isolated from Ashwagandha (W. somnifera) along with other phytochemicals found in this plant including withanone have been shown in molecular docking studies and molecular dynamics (MD) simulations to bind to the Spike protein receptor binding domain as well as the TMPRSS2, thereby blocking or reducing interactions with the host ACE2 receptor [2-4]. In fact, withanone was able to induce changes in the allosteric site of TMPRSS2 similar to the changes reported for camostat (mesylate), an established suppressor of TMPRSS2-dependent infection by SARS-CoV and SARS-CoV-2 [3]. Interestingly, withaferin A has been shown capable of reducing the secretion of various proinflammatory cytokines in a metastatic model of ovarian cancer, including TNFα, IL-6, IL-8, and IL-18.5 So, there is potential that withaferin A treatment can abrogate the intensity of a cytokine storm due to these anti-inflammatory properties. Caffeic acid phenylethyl ester (CAPE) from honeybee propolis was also shown to dock and inhibit TMPRSS2, but MD simulations showed that TMPRSS2 could not retain CAPE in its substrate binding pocket for long [3].

Docking experiments have also shown that curcumin, nimbin, piperine, mangiferin, thebaine, berberine, and andrographolide interact with the SARS-CoV-2 spike glycoprotein and ACE2 receptor and may have utility in restricting viral attachment to host cells [6] Furthermore, resveratrol, quercetin, luteolin, naringenin, zingiberene, and gallic acid all show significant binding affinity towards the ACE2 receptor but not the spike protein and therefore, may be used to explore ACE2-mediated attachment inhibition of SARS-CoV-2 [6].

Mpro/PLpro

Once inside the host cell, viral RNA is translated by the host ribosome into two polyproteins (Pp1a and Pp1ab), which are proteolytically processed by the SARS-CoV-2 Mpro and PLpro for assembly of new viral particles. The Mpro cuts eleven sites at the C-terminus in Pp1a/Pp1ab, and the PLpro cleaves three sites at the N-terminus. As a result of these proteolytic processes, functional polypeptides are released, making Mpro and PLpro attractive targets against which to develop antiviral compounds. Withanone and CAPE are predicted to bind to the substrate-binding pocket of the SARS-CoV-2 Mpro with efficacy and binding energies equivalent to that of N3, an established SARS-CoV-2 Mpro inhibitor [7,8].  Additional natural products that are predicted to bind to the SARS-CoV-2 Mpro include apigenin, maslinic acid, curcumin, glabridin, glycyrrhizic acid, hederagenin, kaempferol, (±)-liquiritigenin, orientin, oleanolic acid, quercetin, rosmarinic acid, ursolic acid, colistin, myricetrin, betulonaldehyde, cerevisterol, hesperidin, and neohesperidin [9-12].

In addition to its proteolytic functions for SARS-CoV-2, PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein, contributing to its separation from interferon responsive factor 3 (IRF3) and an attenuation of type I interferon (IFN) responses.13 PLpro also negatively regulates IRF3 activation by interaction with the STING-TRAF3-TBK1 complex, which interferes with the host response to viral infection.14Platycodin D, baicalin, (–)-epigallocatechin gallate, and procyanidin all have exhibited high binding affinity to SARS-CoV-2 PLpro protein, suggesting the potential utility of these compounds in the treatment of the virus [11].

RdRp

In order to replicate and transcribe the RNA genome, SARS-CoV-2 uses a RdRp complex. This RdRp complex is the target of remdesivir, which has been approved for emergency treatment of patients with COVID-19 in the United States. Natural products that exhibited high binding affinity to RdRp include betulonaldehyde, 14-deoxy-11,12-didehydroandrographolide, and theaflavin 3,3'-digallate [11] Homoharringtonine, an alkaloid originally isolated from C. harringtonia, and emetine, an alkaloid that has been found in ipecac root, can effectively inhibit the replication of SARS-CoV-2 in Vero E6 cells at much lower concentrations than remdesivir [15] Additionally, the combination of emetine and remdesivir exhibited a synergistic inhibitory effect against SARS-CoV-2 replication [15].

Natural products long remain an attractive target for drug researchers to develop novel candidates. Many of the compounds listed above could inspire new iterations for treatment against SARS-CoV-2.

 

References

1. Wang, Z. and Yang, L. Turning the tide: Natural products and natural-product-inspired chemicals as potential counters to SARS-CoV-2 infection. Front. Pharmacol. 11, 1013 (2020).

2. Straughn, A.R. and Kakar, S.S. Withaferin A: A potential therapeutic agent against COVID-19 infection. J. Ovarian Res. 13(1), 79 (2020).

3. Kumar, V., Dhanjal, J.K., Bhargava, P., et al. Withanone and withaferin-A are predicted to interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells. J. Biomol. Struct. Dyn. 1-13 (2020).

4. Balkrishna, A., Pokhrel, S., Singh, H., et al. Withanone from Withania somnifera attenuates SARS-CoV-2 RBD and host ACE2 interactions to rescue spike protein induced pathologies in humanized zebrafish model. Drug Des. Devel. Ther. 15, 1111-1133 (2021).

5. Straughn, A.R. and Kakar, S.S. Withaferin A ameliorates ovarian cancer-induced cachexia and proinflammatory signaling. J. Ovarian Res. 12(1), 115 (2019).

6. Maurya, V.K., Kumar, S., Prasad, A.K., et al. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. Virusdisease 31(2), 179-193 (2020).

7. Kumar, V., Dhanjal, J.K., Kaul, S.C., et al. Withanone and caffeic acid phenethyl ester are predicted to interact with main protease (Mpro) of SARS-CoV-2 and inhibit its activity. J. Biomol. Struct. Dyn. 39(11), 3842-3854 (2021).

8. Jin, Z., Du, X., Xu, Y., et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 582(7811), 289-293 (2020).

9. Maurya, D.K. and Sharma D. Evaluation of traditional ayurvedic Kadha for prevention and management of the novel Coronavirus (SARS-CoV-2) using in silico approach. J. Biomol. Struct. Dyn. 1-16 (2020).

10. ul Qamar, M.T., Alqahtani, S.M., Alamri, M.A., et al. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. J. Pharm. Anal. 10(4), 313-319 (2020).

11. Wu, C., Liu, Y., Yang, Y., et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B 10(5), 766-788 2020).

12. Sampangi-Ramaiah, M.H., Vishwakarma, R., and Shaanker, R.U. Molecular docking analysis of selected natural products from plants for inhibition of SARS-CoV-2 main protease. Curr. Sci. 118(7), 1087-1092 (2020).

13. Shin, D., Mukherjee, R., Grewe, D., et al. Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature 587(7835), 657-662 (2020).

14. Chen, X., Yang, X., Zheng, Y., et al. SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex. Protein Cell 5(5), 369-381 (2014).

15. Choy, K.-T., Wong, A.Y.-L., Kaewpreedee, P., et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in

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