Inhibitors of virus replication: recent developments and prospects

Abstract

The search for inhibitors of viral replication is dependent on understanding the events taking place at the molecular level during viral infection. All the essential steps during the viral life cycle are potential targets for antiviral drugs. Classical inhibitors of herpesvirus replication cause chain termination during viral DNA replication. Similarly, the HIV reverse transcriptase is the major target of anti-HIV compounds. The broad-spectrum antiviral agent ribavirin affects viral nucleic acid replication by multiple mechanisms. Another major enzyme encoded by many viruses is a protease responsible for the processing of virus-encoded polyproteins. The HIV protease has been very successfully targeted, and hepatitis C virus and rhinovirus protease inhibitors are being actively developed. The complex series of interactions during virus entry is a rapidly emerging and promising target for inhibitors of HIV and many other viruses. New anti-influenza drugs inhibit virus release from infected cells. Several stages of the viral life cycle remain incompletely characterized and are therefore poorly exploited in antiviral strategies. These include, among others, the RNA capping reactions catalyzed by many viruses, as well as the membrane association of replication complexes which is common to all positive-strand RNA viruses.

Determinants of RNA-Dependent RNA Polymerase (In)fidelity Revealed by Kinetic Analysis of the Polymerase Encoded by a Foot-and-Mouth Disease Virus Mutant with Reduced Sensitivity to Ribavirin

“…Viral polymerases are important targets for the therapeutic intervention of viral infections (3,10,15,30,33,43). The best example is the reverse transcriptase from human immunodeficiency virus (5,22,23,28,47,49).…”

“…The best example is the reverse transcriptase from human immunodeficiency virus (5,22,23,28,47,49). In most cases, (deoxy)nucleoside analogs that enter the clinic exploit the relaxed fidelity of viral polymerases relative to those of related cellular polymerases (3,10,15,23,28,30,33,43,47). The efficacy of an antiviral nucleoside is compromised by the development of resistance.…”

A Morpholino Oligomer Targeting Highly Conserved Internal Ribosome Entry Site Sequence Is Able To Inhibit Multiple Species of Picornavirus

“…Although effective vaccines for the three serotypes of poliovirus are available, over 100 other enterovirus serotypes (39) and 100 rhinovirus serotypes (11) have been identified, making vaccines and other therapies which rely on an effective adaptive immune response difficult to develop. There are currently no commercially available therapeutics that have been approved by the FDA for use against any of the entero-or rhinoviruses (10,28).…”

“…The smallmolecule compounds in development thus far appear to have limited promise, due variously to high toxicity or low efficacy, stability, or solubility (28). A number of compounds designed to inhibit picornavirus infections through an antisense-mediated mechanism have generated positive preclinical results but are still early in the development process.…”

Inhibitory Influence of the Hexapeptidic Sequence SLIGRL on Influenza A Virus Infection in Mice

“…viral genome, and the packaging and release of progeny virions (Mü ller et al, 2012). This process of IAV replication depends on dozens of host factors, and the majority of conventional antiviral compounds studied to date act via cellular pathways to alter the ability of the virus to propagate (McNicholl and McNicholl, 2001;Takeda et al, 2002;Magden et al, 2005;Guo et al, 2006). However, it is unlikely that SLIGRL directly inhibits IAV propagation pathways because it did not inhibit IAV replication in either chorioallantoic membranes or MDCK cells.…”