Pharmacological and Biological Antiviral Therapeutics for Cardiac Coxsackievirus Infections

Abstract

Subtype B coxsackieviruses (CVB) represent the most commonly identified infectious agents associated with acute and chronic myocarditis, with CVB3 being the most common variant. Damage to the heart is induced both directly by virally mediated cell destruction and indirectly due to the immune and autoimmune processes reacting to virus infection. This review addresses antiviral therapeutics for cardiac coxsackievirus infections discovered over the last 25 years. One group represents pharmacologically active low molecular weight substances that inhibit virus uptake by binding to the virus capsid (e.g., pleconaril) or inactivate viral proteins (e.g., NO-metoprolol and ribavirin) or inhibit cellular proteins which are essential for viral replication (e.g., ubiquitination inhibitors). A second important group of substances are interferons. They have antiviral but also immunomodulating activities. The third and most recently discovered group includes biological and cellular therapeutics. Soluble receptor analogues (e.g., sCAR-Fc) bind to the virus capsid and block virus uptake. Small interfering RNAs, short hairpin RNAs and antisense oligonucleotides bind to and led to degradation of the viral RNA genome or cellular RNAs, thereby preventing their translation and viral replication. Most recently mesenchymal stem cell transplantation has been shown to possess antiviral activity in CVB3 infections. Taken together, a number of antiviral therapeutics has been developed for the treatment of myocardial CVB infection in recent years. In addition to low molecular weight inhibitors, biological therapeutics have become promising anti-viral agents.

The Structure, Pathogenicity and Immunogenicity of Two Virion Fractions Harvested from Cell Cultures Infected with the CA16 Virus

“…In the context of these structural conformations, these two virion fractions displayed distinctive differences that might not be limited to the differences of empty and solid particles. Based on previous data, VP2 plays an important role in the formation of the canyon structure in the virion of Coxsackievirus type B3 (CVB3), which is the structural site for the binding of the virion to its receptor CAR in the cell [29]. In this case, the assumption that the failure of VP2 formation might lead to lower efficacy of the virion interacting with the host cell could explain why the P fraction showed low infectivity.…”

Emerging pharmacologic targets and treatments for myocarditis

“…These models have been used extensively to study the pathogenesis of myocarditis (reviewed in (Fairweather, Stafford, & Sung, 2012)), viral myocarditis (Cheung, et al, 2008;D. Marchant, et al, 2009) and to test the efficacy of new drugs and therapeutic regimens to treat myocarditis (reviewed in (Fechner, Pinkert, Geisler, Poller, & Kurreck, 2011)). Myocarditis models provide a clear timeline of symptoms, with the luxury of knowing the induction date.…”

Biological Antivirals for Treatment of Adenovirus Infections

“…By interacting with the virus, VRTs prevent the virus from binding to cellular receptors and infecting the cell, putting the particles into a non-infectious state (Figure 1). Depending on the virus family, the noninfectious state remains permanently due to formation of altered (A)-particles which is a specific feature of Picornaviridae or it is transient, induced by competitive inhibition [63,64].…”