Biological Function and Application of Picornaviral 2B Protein: A New Target for Antiviral Drug Development

Abstract

Picornaviruses are associated with acute and chronic diseases. The clinical manifestations of infections are often mild, but infections may also lead to respiratory symptoms, gastroenteritis, myocarditis, meningitis, hepatitis, and poliomyelitis, with serious impacts on human health and economic losses in animal husbandry. Thus far, research on picornaviruses has mainly focused on structural proteins such as VP1, whereas the non-structural protein 2B, which plays vital roles in the life cycle of the viruses and exhibits a viroporin or viroporin-like activity, has been overlooked. Viroporins are viral proteins containing at least one amphipathic α-helical structure, which oligomerizes to form transmembrane hydrophilic pores. In this review, we mainly summarize recent research data on the viroporin or viroporin-like activity of 2B proteins, which affects the biological function of the membrane, regulates cell death, and affects the host immune response. Considering these mechanisms, the potential application of the 2B protein as a candidate target for antiviral drug development is discussed, along with research challenges and prospects toward realizing a novel treatment strategy for picornavirus infections.

Coxsackievirus B3 Exploits the Ubiquitin-Proteasome System to Facilitate Viral Replication

“…The CVB3 proteins, 2B and 3A, are both involved in the disruption of the secretory pathway of infected cells and cause rearrangements of cellular membranes contributing to the formation of ROs [ 11 , 12 ]. Furthermore, protein 2B is known to form homotetramers, which act as viroporins and increase membrane permeability, e.g., for Ca 2+ ions [ 17 ]. Protein 3A was previously also described as a viroporin, but it is not as well characterized as protein 2B in this regard [ 18 ].…”

Insights from structural studies of the cardiovirus 2A protein

“…In EMCV this is a 128-amino acid protein, whereas in TMEV it is a short 14–15-amino acid peptide [ 54 ]. 2B encodes a viroporin, which increases cell permeability and thereby can induce viral release and host cell apoptosis [ 57 ]. On the other hand, 2B* has no known function and the main role of frameshifting is thought to be the down-regulation of the other proteins encoded downstream of the frameshift site [ 58 ].…”

Virus-Host Interactions of Enteroviruses and Parvovirus B19 in Myocarditis

“…In addition, the CVB3 viroporin suppresses the cell death stimuli actinomycin D and cycloheximide that would usually activate caspase-3, but a clear connection between Ca 2+ -level manipulation induced by the viroporin and the inhibition of cell death stimuli has still to be established [147]. On the other hand, high concentrations of Ca 2+ in mitochondria lead to initiation of the intrinsic apoptotic pathway by releasing cytochrome c and activating caspase-9 which in turn activates caspase-3 and -7 [150,153,154]. Moreover, CVB3-induced myocarditis in mice exerts ER stress that promotes apoptosis and other cell death mechanisms.…”

“…Thus, viroporins exert extensive effects on ion homeostasis manipulating apoptosis and inflammation signaling. Drugs, siRNA, or shRNA that can inhibit viroporin activity and expression are shown to decrease viral titer in several picornavirus-infected cells [153]. CVB3 and EV71 can additionally regulate miRNAs which has pro-apoptotic effects: CVB3 upregulates miRNA-34a in infected rodent cardiomyocytes [159].…”