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

Abstract

Owing to the recent outbreak of Coronavirus Disease of 2019 (COVID-19), it is urgent to develop effective and safe drugs to treat the present pandemic and prevent other viral infections that might come in the future. Proteins from our own innate immune system can serve as ideal sources of novel drug candidates thanks to their safety and immune regulation versatility. Some host defense RNases equipped with antiviral activity have been reported over time. Here, we try to summarize the currently available information on human RNases that can target viral pathogens, with special focus on enveloped single-stranded RNA (ssRNA) viruses. Overall, host RNases can fight viruses by a combined multifaceted strategy, including the enzymatic target of the viral genome, recognition of virus unique patterns, immune modulation, control of stress granule formation, and induction of autophagy/apoptosis pathways. The review also includes a detailed description of representative enveloped ssRNA viruses and their strategies to interact with the host and evade immune recognition. For comparative purposes, we also provide an exhaustive revision of the currently approved or experimental antiviral drugs. Finally, we sum up the current perspectives of drug development to achieve successful eradication of viral infections.

Keywords: Enveloped single-stranded RNA Viruses; RNases; antiviral drugs; innate Immunity; virus-host interplay.

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