One theoretical option for antiviral therapy is to inhibit the very first step in the viral replication cycle, namely, attachment of the virion to its specific receptor on the plasma membrane of the host cell. This could be accomplished by substances designed to mimic either the cell receptor or the viral ligand. For example, attachment of HIV to its receptor (CD4) can be blocked by soluble CD4 (which binds to the virion) or by a synthetic peptide corresponding to the ligand on the HIV envelope glycoprotein gpl20 (which binds to the cell receptor). A major problem with ligand mimics is that, by saturating the cell receptor, they will presumably interfere with the normal physiologic function of that membrane glycoprotein. Receptor mimics may be safe but would need to be demonstrated not to elicit an autoimmune response.
X-Ray crystallography has provided detailed information on the binding site of a wide range of antiviral agents that block uncoating of picornaviruses. Many of the studies to date have used human rhinovirus type 14 (HRV-14) as a model. Most of the drugs, in spite of their diversity of chemical structure, bind to the same site on HRV-14, namely, a hydrophobic pocket which lies immediately beneath the floor of the canyon that comprises the ligand (receptor-binding site) on the viral capsid protein VP1. Hydrophobic interactions result in deformation of the canyon floor which may inhibit attachment of the virion to its cell receptor but, more importantly, inhibits uncoating of the virion. This is thought to occur by locking VP I into a position that prevents the disassembly of the virion which normally occurs in the acidic environment of the endosome. When administered prophylactically, but not therapeutically, some such antivirals have been claimed to reduce the symptoms of the common colds induced by certain sensitive rhinovirus serotypes but not others. While this is just a start, it does engender some optimism that this new approach to antiviral drug design may eventually provide us with an answer to the question most commonly addressed to virologists, namely, "when will you produce a cure for the common cold?"
Similar research based on a combination of X-ray crystallography and computer modeling is currently being directed at the influenza viruses. The three-dimensional structure of both envelope glycoproteins is known. Sialyloligosaccharides mimicking the receptor for the viral hemagglutinin might be expected to block attachment of virion to host eel], whereas compounds binding the enzyme active site of the viral neuraminidase might inhibit release of new virions from infected cells.
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