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Anti-viral activity of the HIV-1 candidate, L-870812 For those aged 25-44, HIV dropped from the leading cause of death in 1995 to third and fifth leading causes of death in 1996 and 1997 respectively. The age-adjusted HIV death rate of 5.9 deaths per 100,000 is the lowest rate since 1987; the first year mortality data were available for the disease. This dramatic reduction in AIDS related deaths has largely been due to the advent of anti-retroviral agents which prolong AIDS-free HIV infection as well as life-expectancy once AIDS has developed. Despite the success of HIV therapies, there is still a demand for molecules with reduced toxicity and susceptibility to drug resistance. Early HIV therapies have targeted proteases and reverse transcriptase, both of which are crucial viral proteins. The retroviral encoded protein integrase is also a key viral protein required for the insertion of the human immunodeficiency virus type 1 proviral DNA into the host genome. Like proteases and reverse transcriptase, integrase also plays a vital role in the retroviral life cycle, which makes this enzyme an attractive target for the development of new anti-AIDS agents. However, very few inhibitors have been described and until recently none seems to have a potential use in anti-HIV therapy. In exception Merck & Co have developed a series of diketo acids. Unlike previously described inhibitors, the diketo acids inhibit strand transfer at concentrations that are significantly below the concentration required to inhibit either 3' processing or disintegration. Inasmuch as 3' processing of the viral DNA ends is observed in HIV-1 infected cells at concentrations of the inhibitor that block integration and suppress viral replication, the antiviral activity of the diketo acids is due exclusively to their effect on strand transfer. The diketo acids therefore represent a unique class of antiviral agents. One representative of this series, L-870812, increased CD4 counts in SIV-infected rhesus monkeys. More recently a second representative, L-731,988 has been reported to inhibit the replication of 12 HIV type 1 isolates from multiple clades, including primary isolates and cloned viruses. These data suggest that L-731,988 or its derivatives may prove useful on a worldwide basis. L-870812 is currently in phase 1 trial. December, 2002
Adapted from Reinke et al, Antimicrob Agents Chemother 2002 Oct;46(10):3301-3 Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk Projects such as these are overviewed in full DiscoveryDossiers. LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report. This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider. |
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