Late stages in viral replication require important virus-specific processing of certain viral proteins by viral or cellular proteases. Retroviruses, such as HIV, express three genes as precursor polyproteins. Two of these gene products, designated the p55gag and p160gag-pol proteins for their location on the genome, undergo cleavage at several sites by a virally encoded protease to form structural (viral coat) proteins (p17, p24, p8, and p7) and enzymes required for replication (RT, integrase, and protease). The demonstration that HIV protease, a member of the aspartyl protease family of enzymes, is essential for the maturation and infectivity of HIV particles24 has stimulated major research efforts to develop effective inhibitors of this step. These efforts have led to several candidates, some that are on the market and many that are in clinical trials.
To complete the replication cycle, the viral components are assembled into the mature viral particle, or virion. For simple, nonenveloped viruses (e.g., the picornavirus poliovirus), the genome and only a few enzymes are encased by capsid proteins to complete the virion. Other, more complex viruses are enveloped by one or more membranes containing carbohydrate and lipoprotein components derived from the host cell membrane.
Once the mature virion has been assembled, it is ready for release from the cell. The release of certain viruses (e.g., poliovirus) is accompanied by lysis of the host cell membrane and cell death. Some of the enveloped viruses, however, are released by budding or exocytosis, a process involving fusion between the viral envelope and the cell membrane. This process is nearly a reversal of the entry process; the host cell membrane remains intact under these conditions, and the cell may survive.
Chemoprophylaxis is an alternative to active immunization for the prevention of viral infection. With chemoprophy-laxis, one uses a chemical agent that interferes with a step in early viral infectivity. The immune system is not directly stimulated by the drug but is required to respond to any active infection. It would seem that the most successful chemo-prophylactic agents would be those that prevent penetration of the virus into the host cell. In principle, this can be achieved by blocking any of three steps prior to the start of the replication cycle: (a) attachment of the virion to the host cell via its receptor complex, (b) its entry into the cell via en-docytosis, or (c) release of the viral nucleic acid from the protein coat. At present, only a single class of agents affects these early stages of replication.13-16 The adamantanamines (amantadine and rimantadine) have been approved for controlling influenza type A infection. These drugs appear to interfere with two stages of influenza type A viral replication: preventing the early stage of viral uncoating and disturbing the late stage of viral assembly. Clinical studies have shown that amantadine and rimantadine are effective in both prophylaxis and treatment of active influenza type A infection.
Amantadine and rimantadine are both drugs that interfere with penetration of host cells by viruses and block early-stage replication. Amantadine, 1-adamantanamine hydrochloride (Symmetrel), and its a--methyl derivative rimantadine, a-methyl-1-adamantane methylamine hydrochloride (Flumadine), are unusual caged tricyclic amines with the following structures:
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