Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses

Figures & data

Figure 1. The Viral Life Cycle. The life cycle of positive single-strand RNA [(+)ssRNA], negative single-strand RNA viruses [(-)ssRNA] and also HIV are indicated. Normally, viruses firstly enter into the host cell by either fusion or endocytosis, then the viral genome is replicated and the viral polyproteins are translated within the cytoplasm. Many (+)ssRNA viruses can replicate and be transcribed in special DMV. Finally, virion assembly and release takes place. The life cycle for (+)ssRNA viruses are shown in red color and for (-)ssRNA in blue. For HIV, the genome will be reverse transcribed into dsDNA and then integrated into the host genome, as shown in light blue color

Figure 2. Host-virus interplay. (a). Pathogen-associated molecular patterns (PAMPs). The three most common PAMPs in case of viral intrusion are shown. From left to right, they are RLRs, TLRs and NLRs respectively. Different receptors can recognize various RNAs produced by viruses. Normally, after the recognition, IFNs and cytokines are induced through a series of signal cascades. (b). OAS/RNase L pathway. The related processes in response to dsRNA are shown. An IFN-induced 2–5A synthetase (OAS) is expressed to synthesize 2′5′ oligoadenylates (2–5A), which activate RNase L, and then small RNAs cleaved by active RNase L can exert multiple functions to fight viruses. The related processes are shown. (c). PKR pathway. The important processes are indicated. PKR is also an IFN-induced, dsRNA-activated protein kinase. Once active, PKR can phosphorylate the eukaryotic translation initiation factor (eIF2α), which later suppresses viral translation and induces stress granules (SGs) formation

Table 1. Anti-ssRNA viral mechanisms targeted by RNases

RNases	Proposed Mechanism (tested in vitro or in vivo)^a	ssRNA Viruses			Refs
		Name^b	ENV^c	Sense
RNase A	• Inhibits replication (in PHA-stimulated T cell blasts)	HIV-1	Y	+	^[Citation223]
RNase 2 /EDN	• Inhibits replication (in PHA-stimulated T cell blasts)	HIV-1	Y	+	^[Citation204,Citation223]
	• Degrades viral RNA (in total RNA from infected ACH2 cells)
	• Ribonuclease-dependent activity (in RhMk cells)	PIV	Y	-	^[Citation19]
	• Ribonuclease-dependent activity (in HEp-2 cells)	RSV-B	Y	-	^[Citation19,Citation212]
	• A unique loop helps its interaction with viral capsid and penetration into the virion (in HEp-2 cells)
RNase 3 /ECP	• Ribonuclease-dependent activity (in HEp-2 and THP-1 cells)	RSV-B	Y	-	^[Citation208,Citation209]
RNase 5 /ANG	• Inhibits replication (in PHA-stimulated T cell blasts or PBMCs)	HIV-1	Y	+	^[Citation220,Citation223]
BS-RNase	• Inhibits replication (in H9 leukaemia cells)	HIV-1	Y	+	^[Citation224]
Onconase	• Inhibits replication (in H9 and U937 leukaemia cells)	HIV-1	Y	+	^[Citation224,Citation230,Citation231]
	• Inhibits replication by removal of the transcription primer (tRNA synthesized in vitro)
RNase L	• OAS/RNase L pathway is necessary for IFN-α but not for IFN- γ to inhibit viral replication (pancreatic islet from mouse)	CV-B4	N	+	^[Citation268]
	• Inhibits viral RNA synthesis (in LS1 cells)	EMCV	N	+	^[Citation20,Citation247,Citation269,Citation270]
	• Increases the antiviral activity of IFN when overexpressed (in LS1 cells)
	• RNase L helps to amplify IFN-β signalling (in mouse)
	• Autophagy (in MEFs)
	• Apoptosis
	• UA and UU dinucleotides in viral RNA is the main cleavage site of RNase L (HCV mRNA synthesized in vitro)	HCV	Y	+	^[Citation244,Citation271]
	• A small RNA cleaved by RNase L activates RIG-I and thereby promotes IFN-β response (in mouse)
	• Inhibits HIV-1 replication by 8 times (in Jurkat cells)	HIV-1	Y	+	^[Citation245]
	• RNase L cleaves viral RNAs in absence of viral resistance protein NS1 (in A549 cells)	IAV	Y	-	^[Citation272]
	• IFN-γ-mediated inhibition in human epithelial cells involves the OAS/RNase L pathway (in HEp-2 cells)	RSV	Y	-	^[Citation246]
	• RNase L helps to amplify IFN-β signalling (in mouse)	SeV	Y	-	^[Citation20,Citation242,Citation273]
	• SGs formation (in HT1080 cells)
	• Autophagy (in MEFs)
	• Contributes to IFN-α/β–mediated protection (in MEFs)	SINV	Y	+	^[Citation274,Citation275]
	• Interferes with the synthesis of minus strands of heat-resistant strain (in MEFs)
	• Autophagy (in MEFs)	VSV	Y	-	^[Citation247]
	• Cleaves viral genomic RNA (in vitro)	WNV	Y	+	^[Citation276,Citation277]
	• Contributes to IFN-mediated protection (in CD11b^+ cells)
Regnase/MCPIP1	• Inhibits replication (in hepatoma cells)	HCV	Y	+	^[Citation278]
	• Degrades viral RNA (in vitro)
	• Degrades viral RNA (in vitro)	DENV	Y	+	^[Citation263]
		JEV	Y	+
RNase P	• Cleaves HCV RNA transcripts (in vitro)	HCV	Y	+	^[Citation264]
Binase	• Inhibits replication (in MRC5 cells)	MERS-CoV	Y	+	^[Citation267]
	• Direct action on the viral mRNA (in A549 and MDCK-II cells)	IAV	Y	-	^[Citation265,Citation266]

^aA549: human lung adenocarcinoma epithelial cells; HEp-2: human laryngeal carcinoma/human type 2 epithelial cells; MDCK-II: Madin-Darby canine kidney epithelial cells; MEF: mouse embryonic fibroblasts; MRC5: human fetal lung fibroblasts; PBMC: peripheral blood mononuclear cells; PHA: phytohemagglutinin; RhMk: rhesus monkey kidney; THP-1: a human monocytic cell line.

^bCV-B4: Coxsackie virus B4; DENV: Dengue virus; EMCV: Encephalomyocarditis virus; HCV: Hepatitis C virus; HIV: Human Immunodeficiency virus; IAV: Influenza A virus; JEV: Japanese Encephalitis virus; MERS-CoV: Middle East Respiratory Syndrome Coronavirus; PIV: Human Parainfluenza virus; RSV: Respiratory Syncytial virus; SeV: Sendai virus; SINV: Sindbis virus; VSV: Vesicular Stomatitis virus; WNV: West Nile virus.

^cENV: Enveloped; Y: Yes; N: No.

Table 2. Main available drugs or candidates against enveloped ssRNA viruses

Virus		Antiviral Mechanisms	Status	Representative Drugs^d
(+) ssRNA virus	SARS -CoV-2	• Entry inhibitor	Investigational	• Leronlimab
		• RNA polymerase inhibitors	Investigational /conditionally approved	• Favipiravir[323] • GS-441524	• Remdesivir
		• Inosine-5-monophosphate dehydrogenase (IMPDH) Inhibitor	Investigational	• Merimepodib[324]
	HCV	• NS3/4A protease inhibitors	Approved	• Asunaprevir • Boceprevir • Glecaprevir • Grazoprevir	• Paritaprevir • Simeprevir • Telaprevir • Voxilaprevir
			Investigational	• Faldaprevir	• Vedroprevir
		• NS5B polymerase inhibitors	Approved	• Dasabuvir	• Sofosbuvir
			Investigational	• Beclabuvir	• Uprifosbuvir
		• NS5A inhibitors	Approved	• Elbasvir • Daclatasvir • Ledipasvir	• Ombitasvir • Pibrentasvir • Velpatasvir
			Investigational	• Odalasvir • Ravidasvir	Ruzasvir
		• Interferon α/β receptor agonists	Approved	• Peginterferon α2a • Peginterferon α2b
		• Broad-spectrum activity	Approved	• Ribavirin
	HIV	• Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI)	Approved	• Abacavir • Didanosine • Emtricitabine • Lamivudine	• Stavudine • Tenofovir disoproxil • Zalcitabine • Zidovudine
			Investigational	• Elvucitabine	• Racivir
		• Non-nucleoside reverse transcriptase inhibitors (NNRTI)	Approved	• Delavirdine • Doravirine • Efavirenz	• Etravirine • Nevirapine • Rilpivirine
			Investigational	• Atevirdine • Calanolide A	• UC-781
		• Protease inhibitors	Approved	• Amprenavir • Atazanavir • Darunavir • Fosamprenavir • Indinavir	• Lopinavir • Nelfinavir • Ritonavir • Saquinavir • Tipranavir
			Investigational	• TMC-310911
		• Integrase inhibitors	Approved	• Bictegravir • Dolutegravir	• Elvitegravir • Raltegravir
		• Fusion inhibitor	Approved	• Enfuvirtide
		• Entry inhibitors	Approved	• Maraviroc	• Ibalizumab
			Investigational	• Cenicriviroc	• Leronlimab
		• Others	Investigational	• BMS-488043 • Dexelvucitabine • Fiacitabine	• Lobucavir • Sorivudine
(-) ssRNA virus	RSV	• Fusion inhibitor	Approved	• Palivizumab
		• Broad-spectrum activity	Approved	• Ribavirin
	Influenza virus	• CAP endonuclease inhibitor	Approved	• Baloxavir marboxil
		• Neuraminidase inhibitors	Approved	• Oseltamivir • Peramivir		• Zanamivir
			Investigational	• Laninamivir
		• RNA synthesis inhibitors	Approved	• Rimantadine
			Experimental	• Triazavirin
		• Fusion inhibitor	Investigational	• Umifenovir

^dSummary from DRUGBANK, category of Antiviral Agents (https://www.drugbank.ca/categories/DBCAT000066) when no other reference is provided.³⁴¹

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