Discovery and in vitro development of AIDS antiviral drugs as biopharmaceuticals.

The goal of developing an effective drug against HIV-1 and AIDS has been approached by several routes, with enough encouraging results to stimulate further efforts. Compounds active against HIV-1 have been discovered for many of the functions in the reproductive cycle recognized as virus-specific targets. Discoveries have been made in cell-based assays as well as mechanistic assays, and the value of both types of assays in the drug discovery process has been discussed. Although the final test of a drug's efficacy comes in the clinical experience, submission of an antiviral compound to an in vitro developmental gauntlet can save much time, effort, expense, and human resource in the in vivo developmental regimen required prior to human use. Emergence of viral resistance to drugs in several structural classes has compromised their clinical efficacy, suggesting that development of other potential drugs in those classes may not be good investments. Strains of HIV-1 resistant to specific compound classes are used to categorize new active discoveries for possible developmental exclusion, and defining the mechanism of action of such a new compound may confirm the discouraging judgement. On the other hand, novel compounds which exhibit a broad range of activity in drug-resistant and other HIV-1 strains deserve greater scrutiny. Clinicians most likely will be hesitant to treat patients with compounds shown to act on virus-cell surface interactions, given the failure in the past of several such compounds in clinical studies. But a compound shown to have a unique and novel mechanism of action will be looked upon more favorably, and surviving other tests of potency, solubility, and stability will be unhesitatingly presented for in vivo development. The partial successes of drugs currently in clinical use against AIDS offers great encouragement that other more-effective, less-toxic drugs will be found. Exquisite techniques for identifying new targets on virus gene products, the selection of compounds on activity paradigms, and the enormous variety of compounds becoming available through synthesis libraries, all offer opportunities for anti-HIV drug discovery, which, in our view, cannot fail to present potent antiviral compounds which will survive the rigorous preclinical and clinical tests leading to a drug effective against AIDS.