       Document 0483
 DOCN  M9630483
 TI    Discovery and in vitro development of AIDS antiviral drugs as
       biopharmaceuticals.
 DT    9603
 AU    Rice WG; Bader JP; Laboratory of Antiviral Drug Mechanisms, National
       Cancer; Institute, Frederick Cancer Research and Development Center,;
       Maryland 21701-1201, USA.
 SO    Adv Pharmacol. 1995;33:389-438. Unique Identifier : AIDSLINE
       MED/96099876
 AB    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.
 DE    Acquired Immunodeficiency Syndrome/*DRUG THERAPY  Antiviral
       Agents/*PHARMACOLOGY  Drug Design  Human  HIV-1  In Vitro
       Pharmaceutical Services  JOURNAL ARTICLE  REVIEW  REVIEW, ACADEMIC

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

