Selective inhibitors of picornavirus replication

Abstract

Picornaviruses cover a large family of pathogens that have a major impact on human but also on veterinary health. Although most infections in man subside mildly or asymptomatically, picornaviruses can also be responsible for severe, potentially life-threatening disease. To date, no therapy has been approved for the treatment of picornavirus infections. However, efforts to develop an antiviral that is effective in treating picornavirus-associated diseases are ongoing. In 2007, Schering-Plough, under license of ViroPharma, completed a phase II clinical trial with Pleconaril, a drug that was originally rejected by the FDA after a New Drug Application in 2001. Rupintrivir, a rhinovirus protease inhibitor developed at Pfizer, reached clinical trials but was recently halted from further development. Finally, Biota's HRV drug BTA-798 is scheduled for phase II trials in 2008. Several key steps in the picornaviral replication cycle, involving structural as well as non-structural proteins, have been identified as valuable targets for inhibition. The current review aims to highlight the most important developments during the past decades in the search for antivirals against picornaviruses.

Targeting Norovirus: Strategies for the Discovery of New Antiviral Drugs

“…However, until now there is only experimental data confirming the NTPase but not the helicase activity of this nonstructural protein of norovirus (Hardy, 2005). , 2008a;De Palma et al, 2008c;Norder et al, 2011) could as well be inhibitors of the NTPase of norovirus. The multiple mechanisms through which compounds could inhibit the helicase/NTPase have been extensively described elsewhere .…”

“…The inhibitors of the 3C protease of picornavirus, such as ruprintrivir, may potentially inhibit the norovirus protease given the overall similarity between the proteases of these viruses. (Binford et al, 2005;De Palma et al, 2008c;Leyssen et al, 2008).…”

Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket

“…As of today no therapeutics have been approved for the treatment of these infections (De Palma et al, 2008;Schmidtke, 2011)(De Palma et al, 2008;Rollinger and Schmidtke, 2011). Several capsid-binding inhibitorsmolecules (CIs) are being investigated as promising drug candidates (Andries et al, 1991;Diana, 2003;Makarov et al, 2005;Watson et al, 2003) (Andries et al, 1991;Diana, 2003;Makarov et al, 2005;Watson et al, 2003), the most developed ones being pleconaril and vapendavir (Diana et al, 1995;Feil et al, 2012) (Diana et al, 1995;Feil et al, 2012).…”

“…They cause a wide range of acute and chronic diseases such as respiratory infections, meningitis, pancreatitis, encephalitis, and myocarditis (Pallansch and Roos, 2007;Turner and Couch, 2007). As of today no therapeutics have been approved for the treatment of these infections (De Palma et al, 2008;Rollinger and Schmidtke, 2011). Several capsid-binding molecules (CIs) are being investigated as promising drug candidates (Andries et al, 1991;Diana, 2003;Makarov et al, 2005;Watson et al, 2003), the most developed ones being pleconaril and vapendavir (Diana et al, 1995;Feil et al, 2012).…”

Prevalência de vírus respiratórios em crianças de creche com sintomas de infecções respiratórias agudas

“…Um grande número de agentes experimentais foi testado para suas atividades anti-picornavírus, com resultados pouco animadores, porém alguns têm sido submetidos à fase inicial de testes clínicos (SMITH et al, 1986;DE PALMA et al, 2008).…”