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1996-02-27
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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).