[Antiviral agents that act in the early phases of the viral cycle]

The development of antiviral chemotherapy against human immunodeficiency virus (HIV) and herpesvirus suffers from two main problems: the toxic side effects and the emergence of drug resistance associated to the continuous treatment of immunocompromised patients. A variety of compounds targeted at the early stages of the viral replicative cycle, such as virus adsorption, entry and uncoating, appear to be excellent candidates for combination therapy with the presently licensed drugs in clinical use. One approach has been to create soluble forms of cellular receptors that might block initial binding of virus to cells. Various forms of recombinant CD4, including truncated molecules and peptides as well as CD4-immunoglobulin and CD4-albumin constructs, were assayed against in vitro and in vivo HIV infection. Polyanionic compounds, including polysulfates, polysulfonates, polycarboxylates and polyoxometalates, were highly potent and selective inhibitors of the in vitro replication of HIV and other enveloped viruses. They inhibited virus replication at a concentration of 0.1-1 microgram/ml, while not being cytotoxic at up to 10000-fold higher concentration. Polysulfates can be obtained from natural sources such as marine algae and made available in large quantities at reasonable cost. Some disadvantages of polyanionic substances in vivo (low oral bioavailability, anticoagulant properties, thrombocytopenia) can be circumvented by a topical formulation to prevent sexually transmitted infections. Other promising compounds are the bicyclams, postulated to interact with HIV uncoating. Bicyclams achieve in vitro selectivity indexes of 100,000 and higher but their efficacy in animal models still remains to be demonstrated.