Natural Products with Potential to Treat RNA Virus Pathogens Including SARS-CoV-2

Abstract

Three families of RNA viruses, the Coronaviridae, Flaviviridae, and Filoviridae, collectively have great potential to cause epidemic disease in human populations. The current SARS-CoV-2 (Coronaviridae) responsible for the COVID-19 pandemic underscores the lack of effective medications currently available to treat these classes of viral pathogens. Similarly, the Flaviviridae, which includes such viruses as Dengue, West Nile, and Zika, and the Filoviridae, with the Ebola-type viruses, as examples, all lack effective therapeutics. In this review, we present fundamental information concerning the biology of these three virus families, including their genomic makeup, mode of infection of human cells, and key proteins that may offer targeted therapies. Further, we present the natural products and their derivatives that have documented activities to these viral and host proteins, offering hope for future mechanism-based antiviral therapeutics. By arranging these potential protein targets and their natural product inhibitors by target type across these three families of virus, new insights are developed, and crossover treatment strategies are suggested. Hence, natural products, as is the case for other therapeutic areas, continue to be a promising source of structurally diverse new anti-RNA virus therapeutics.

Figure 1.

Life cycle of coronaviruses as represented by the SARS-CoV-1/2 and MERS-COV viruses. The Roman numerals in the figure refer to entries in Table 2. The “T” symbol indicates a target with potential for developing an inhibitor.

Figure 2.

Life cycle of Flaviviridae as represented by the dengue virus. The roman numerals in the figure refer to entries in Table 3. The “T” symbol indicates a target with potential for developing an inhibitor.

Figure 3.

Life cycle of filoviruses as represented by the Ebola virus. The Roman numerals in the figure refer to the entries in Table 4. The “T” symbol indicates a target with potential for developing an inhibitor.

Figure 4.

Schematic diagrams for the genomes of coronavirus SARS-CoV-2 (Coronaviridae), Dengue virus (Flaviviridae), and Ebola virus (Filoviridae). The genomes of Coronaviridae and Flaviviridae are composed of single-strand positive-sense RNA whereas those of the Filoviridae are composed of a single-strand of negative-sense RNA. Genes labeled by Roman numerals encode potential druggable protein targets mentioned in this review, and accord to the same Roman numerals used in Figures 1–3 and Tables 2–4. Capsid protein (pink), spike protein (red), polymerase (brown), enzyme (orange), structural protein (green), envelope protein (yellow), cofactor/activator (blue), others/undefined protein (grey).

Figure 5.

Inhibitors of viral structural proteins of A) Coronaviridae, B) Flaviviridae, or C) Filoviridae. The following are natural products: griffithsin (PDB: 2GTY), emodin, nordihydroguaiaretic acid, ellagic acid, gallic acid, cyanovirin-N (11, PDB: 2EZM) and natural product derivatives: PG545, 8, 9, 10

Figure 6.

Inhibitors of viral proteases 3CLpro (A), PLpro (B), or NS3 (C). The following are natural products: herbacetin, pectolinarin, rhoifolin, tomentin B, hirsutenone, cryptotanshinone, psoralidin, ganodermanotriol, ivermectin and natural product derivatives: Rupintrivir.

Figure 7.

Inhibitors of viral replicase complex component RdRp. Shown here are compounds that are inhibitors of Coronaviridae, Flaviviridae, Filoviridae, or of multiple families. The following are natural products: mycophenolic acid and sinefungin and natural product derivatives: Remdesivir, Favipiravir, Ribavirin, Galdesivir, 3-D-N4-hydroxycytidine, BCX4430.

Figure 8.

Inhibitors of viral helicase. All of these are natural products.

Figure 9.

Inhibitors of selected accessory proteins. Celgosivir is a derivative of the natural product castanospermine.

Figure 10.

Inhibitors of host cysteine proteases cathepsin L/B or serine proteases TMPRSS2/4. The following are natural products: aprotinin, gallinamide A, nicolaiodesin C, grassypeptolide, leupeptin, tokoramide A, miraziridine A, E-64d and natural product derivatives: 41, CA074.

Figure 11.

Inhibitors of other selected targets with activity to RNA viruses. All of these compounds are natural products.

Figure 12.

Inhibitors with demonstrated antiviral activity without a known target or mechanism of action. All of these compounds are natural products.