Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-01-04
2000-04-04
Lambkin, Deborah C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514442, 514440, 514436, 549 35, 549 36, 549 37, 549 38, 549 39, 549 21, A61K 31385, C07D33902, C07D40900
Patent
active
060462280
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Numerous compounds are currently undergoing in vitro development and clinical evaluation as potential drugs for the treatment of human immunodeficiency virus type 1(HIV-1) infection and the associated acquired immunodeficiency syndrome (AIDS). Historically, compounds directed toward inhibition of virus attachment to target cells have failed clinically due to their toxicities at effective antiviral concentrations, poor absorption from the gut or lack of broad spectrum activities against clinical stains of HIV-1. Similarly, the approach to use synthetic nucleoside analogs, such as 3'-azido-3'-deoxythymidine (AZT), or the complex class of non-nucleoside compounds to target the HIV-1 reverse transcriptase (RT) enzyme has been plagued by the emergence of drug-resistant strains. HIV-1 protease has also become the focus of much attention as a potential antiviral target due to its critical role in the post-integration processing of viral precursor polypeptides to their mature products, a process required for maturation of virus particles into infectious virions. Unfortunately, the vast majority of designed inhibitors of protease are substrate-based peptide structures that typically demonstrate poor bioavailability, short serum half-lives and overt cytotoxicity at effective antiviral concentration.
In addition, most antiviral drugs used to control the spread of HIV-1 have also proven to become compromised under the selection pressure of the drug, as the virus soon mutates to a drug-resistant strain. This tendency to develop drug resistance is a survival strategy used by many classes of viruses and is particularly pronounced among the members of the retrovirus family. One way to defeat this survival strategy is to focus on drugs attacking specific elements of the virus that are intolerant to mutations. Such elements can be identified by searching the proteins present in all viruses within the virus class to identify common or highly conserved structures.
Retroviruses have a highly conserved structure in their nucleocapsid (NC) proteins. All NC proteins of the Oncoviridae and Lentiviridae subfamilies of Retroviridae contain sequences of 14 amino acids with 4 invariant residues, Cys(X).sub.2 Cys(X).sub.4 His(X).sub.4 Cys, which chelate zinc through histidine imidazole and cysteine thiolates with a K.sub.d less than 10.sup.-13. These structures are referred to as retroviral CCHC zinc fingers, and are one of the most highly conserved features of retroviruses (Henderson, et al., J. Biol. Chem. 256:8400-8406 (1981)). Examples of retroviruses which possess at least one CCHC type zinc finger per nucleocapsid protein include, but are not limited to, HIV-1, HIV-2, SIV, BIV, EIAV, Visna, CaEV, HTLV-1, BLV, MPMV, MMTV, RSV, MuLV, FeLV, BaEV, and SSV. Due to their highly conserved nature, it is thought that CCHC zinc fingers perform an essential function in viral infectivity. In fact, it has been disclosed that mutations of the chelating residues (CCHC) in the zinc fingers yield a non-infectious virus (Gorelick, et al., J. Virol. 64:3207-3211 (1990)).
HIV-1 NC contains two zinc finger domains separated by only 7 amino acids. HIV-1 NC proteins are synthesized as part of the Pr55.sup.gag and Pr160.sup.gag-pol precursor polyproteins, and the fingers within these precursor molecules are required for packaging of viral genomic RNA and to form the core structure of the immature virion. Subsequent proteolytic processing of these precursors yields the mature p7NC protein, and the fingers of the NC protein are required for the virus to fully execute reverse transcription in the next target cell. Hence, treating of HIV-1 infected individuals with antiviral compounds that target the mutationally intolerant retroviral zinc finger may provide for multiple inhibitory effects on the viral replication cycle while attenuating the emergence of drug-resistant HIV-1 strains.
Widespread acceptance of the CCHC zinc finger as an antiviral target has not been forthcoming due to a lack of identification of compounds that sel
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Baker David C.
Henderson Louis E.
Rice William G.
Schultz Robert R.
Lambkin Deborah C.
The United States of America as represented by the Department of
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