Current Status of Anti-Picornavirus Therapies

Abstract

Picornaviruses are important human pathogens causing severe morbidity and some mortality with the potential to cause worldwide crippling disease. Currently, there are few treatments for many of the viruses in the Picornaviridae, For rhinoviruses, there are no approved treatments, although ruprintrivir looks promising in clinical trials and pyridazinyl oxime ethers may prove useful. Poliovirus treatments are needed to supplement the World Health Organization's polio eradication plan in order to treat infections caused by reversion of the attenuated vaccine virus and to supplement vaccine coverage control in polio endemic areas. However, no promising compounds for treatment of poliovirus have been developed due to the efficacy of the vaccines in use. Broad-spectrum inhibitors developed for other picornavirus may be useful for poliovirus infections. Coxsackievirus infections in children and in infants are being treated with pleconaril with some efficacy in reducing mortality and improving recovery, albeit the treatment is often on a compassionate use basis. There are no therapies for echovirus infections. Very little drug discovery research is being done to develop inhibitors for echovirus infections, probably due to the broad-spectrum inhibition exhibited by capsid binding agents and protease inhibitors discovered for treatment of other picornaviruses. For example, pyridazinyl oxime ethers are inhibitory to most echoviruses. Treatments for enterovirus infections are also limited, although in a small clinical trial, milrinone seemed to reduce mortality and improve recovery from EV71-induced pulmonary edema. Thus, these results strongly emphasize the need for the development of potent and nontoxic compounds for the treatment of picornavirus infections.

A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection

“…To date, several anti-enterovirus compounds that target viral or cellular factors have been identified (reviewed by Barnard, 2006;Chen et al, 2008;Rotbart, 2002). Among the compounds with anti-PV activity, guanidine hydrochloride (GuHCl), brefeldin A and enviroxime inhibit replication steps with known targets.…”

The Crystal Structure of Coxsackievirus B3 RNA-Dependent RNA Polymerase in Complex with Its Protein Primer VPg Confirms the Existence of a Second VPg Binding Site on Picornaviridae Polymerases

“…Furthermore, CVB3 causes acute infections in neonates and infants leading to febrile illness and meningitis, as well as hepatitis and coagulopathy in severe cases (71). To date, no vaccine or specific anticoxsackievirus drug is approved (2,60).…”

Effect of consecutive alternating administration (CAA) of a triple anti-enteroviral combination on Coxsackievirus B1 neuroinfection in mice

“…Doing so could result in reduced risk of acquired diabetes and other severe forms of enterovirus-induced infections (Hyöty et al, 1995;Hyöty and Taylor, 2002;Galabov and Angelova, 2006 Currently, clinically effective antivirals for treating enteroviral infections do not exist. Despite the large number of compounds that are effective in vitro (Barnard, 2006;De Palma et al, 2008), anti-enteroviral chemotherapeutics for clinical use have not yet been approved, and the results of clinical trials of the most active antivirals could be considered as modest. The unsatisfactory in vivo effectiveness of enteroviral replication inhibitors has been ascribed to the rapid development of drug resistance (Loddo, 1980;Melnick et al, 1961) by initially drug-sensitive viruses.…”