Identification of a Series of Compounds with Potent Antiviral Activity for the Treatment of Enterovirus Infections

Abstract

Rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. Other members of the genus can cause life-threatening acute neurological infections. There is currently no antiviral drug approved for the treatment of such infections. We have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, Coxsackie virus, poliovirus, and enterovirus-71. The mechanism of action of the compounds has been established as inhibition of a lipid kinase, PI4KIIIβ. Inhibition of hepatitis C replication in a replicon assay correlated with enterovirus inhibition. KEYWORDS: antiviral, enterovirus, HCV, inhibitor, PI4KIIIβ O ver the last 15 years, evidence has gathered that viral infections of the respiratory tract are a major cause of exacerbations in both chronic obstructive pulmonary disease (COPD) 1 and asthma. 2 Of these infections, half to two-thirds are caused by human rhinovirus (HRV), the most well-known etiologic agent of the common cold.3 While these infections are merely inconvenient in otherwise healthy individuals, exacerbation of the symptoms of COPD and asthma are serious, leading to very large numbers of hospitalizations and significant mortality. In fact, the prevalence of COPD is increasing rapidly, and it is predicted to become the third leading cause of death globally by 2030. 4 Hence, the identification of compounds that can interfere with rhinovirus replication may lead to drugs that have important clinical value in the management of a growing medical need.In the past, several drug candidates have been progressed into clinical trials for the treatment of HRV infections. These include Rupintrivir, 5 a viral 3C protease inhibitor, and a number of compounds that prevent virus entry into cells by binding to the viral capsid: Pirodavir, 6 Pleconaril, 7 and BTA798. 8 Only the latter of these is currently in clinical development, the others having been terminated due to lack of clinical efficacy or unacceptable side effects.As part of an antiviral program directed toward hepatitis C (HCV), we identified a series of imidazo-pyrazines with modest (micromolar) activity in a genotype 1b replicon screen ( Figure 1). These compounds were derived from a BioFocus SoftFocus library (SFK28) initially designed as potential kinase inhibitors.Additional screening of the imidazo-pyrazines against a panel of other viruses revealed similar activity against the Enteroviruses, a genus of the Picornaviridae family, including HRV, polio virus (PV), and Coxsackie virus (CV). In most cases, the compounds were 3−5-fold more active against enteroviruses, which, in common with HCV, are positive-sense singlestranded RNA (+ssRNA) viruses. The compounds proved inactive against other RNA, DNA, and retroviruses and were not cytotoxic at antiviral concentrations, indicating a specific and selective antiviral effect.Enteroviruses present a range of threats to human health, from the common cold ...

Phosphatidylinositol 4-kinases: Function, structure, and inhibition

“…BF738735 was also active against HCV 1b with EC 50 ¼56 nM. MacLeod and colleagues reported that this compound was also based on a hit from high throughput screening [147]. Enviroxime itself was also proven to inhibit PI4K class III enzymes although with rather low selectivity [89].…”

Hydrophobic pocket targeting probes for enteroviruses

“…3,10,29,42 However, probes that replace the natural hydrophobic moiety, but do not compromise the infectivity and uncoating of the virus, could also act as potential markers and tools to study the function of the hydrophobic pocket. As far as we know, this is the first study to specifically label and visualize the pocket by using both gold nanoclusters and a fluorescent dye as visualizing tags.…”

Lipid Tales of Viral Replication and Transmission

“…Indeed, in vitro studies, acutely inhibiting PI4KIIIβ or PI4KIIIα kinases with small molecules such as PIK93, depleting them from the host cell, overexpressing kinase dead mutants or ectopically expressing phosphatases to lower PI4P levels, have all been shown to be successful in blocking viral RNA synthesis in many different types of infections [22,23,31,42,43], while not significantly affecting cell viability. The latter is likely due to compensation of host PI4P needs by redundant enzymatic activities provided by other, such as type II, PI4 kinase family members [28].…”