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Styrylquinolines : A New Family of HIV Integrase Binding Inhibitors Shows Synergy with Other Antiretroviral Drugs
Mar 8, 2005, 15:03, Reviewed by: Dr.
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These results are significant because they suggest a way of combating the emergence of drug-resistant strains of human immunodeficiency virus type 1 (HIV-1) that has arisen through the use of HIV-1 inhibitors such as reverse transcriptase and protease inhibitors, thus supporting the introduction of integrase inhibitors as a potential weapon in the fight against drug resistant viral strains.
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By Akanksha, Pharmacology Correspondent,
BioAlliance Pharma, a biopharmaceutical company focused on the field of drug resistance, announced today results presented at the 12th Conference on Retroviruses and Opportunistic Infections (CROI) held in Boston, suggesting a new way to overcome growing HIV resistance.
The results demonstrate that styrylquinolines (SQLs), a new family of integrase binding inhibitors being developed by the company, show synergy with reverse transcriptase inhibitors (zidovudine and nevirapine) and with another family of integrase inhibitors, strand transfer inhibitors known as Diketoacids.
The in vitro study suggests that SQLs could be used in combination with other antiretroviral drugs in multi therapy regimens and illustrates the potential for developing an alternative class of integrase inhibitors to overcome developing HIV resistance.
Today's report is part of an ongoing investigation of SQLs based on a lead compound (BA011FZ041). The research team, which came from the Ecole Normale Superieure de Cachan, as well as BioAlliance Pharma, has previously shown (Journal of Virology, Vol. 78, No. 11: 5728-5736, 2004) for the first time that integrase targeting molecules may act prior to integration and affect the accumulation of DNA during reverse transcription.
In addition, the research team has also shown (Molecular Pharmacology, Vol. 66, No. 4: 783-788, 2004) that SQLs specifically and efficiently inhibit nuclear import of integrase. Moreover, the team demonstrated the in vitro absence of cross-resistance between SQLs and reverse transcriptase inhibitors or Diketoacid derivatives.
These results are significant because they suggest a way of combating the emergence of drug-resistant strains of human immunodeficiency virus type 1 (HIV-1) that has arisen through the use of HIV-1 inhibitors such as reverse transcriptase and protease inhibitors, thus supporting the introduction of integrase inhibitors as a potential weapon in the fight against drug resistant viral strains.
"In all our experiments, the combination of the BA011FZ041 lead compound never led to antagonistic effect with either reverse transcriptase inhibitors or the integrase inhibitors tested," said Jean-Francois Mouscadet, Director of Research at the Laboratory for Biotechnology and Applied Pharmacology, Ecole Normale Superieure de Cachan, France, and lead investigator for the study.
"On the contrary, synergy was observed with all three compounds, a result which is consistent with independent mechanisms of inhibition. Moreover, synergy with late-acting strand transfer inhibitors most likely originates from the early anti-IN effect of SQLs which act before viral DNA can reach the cell nucleus, thus reinforcing the interest for this novel antiviral mechanism."
"This study again confirms the value of our NCE program and the potential of styrylquinolines as a promising route to the development of integrase inhibitors," said Dominique Costantini, MD, president and CEO of BioAlliance Pharma. "Whether synergy between these compounds in vitro will translate into clinical benefits will need to be addressed in the context of clinical trials, which we would hope to advance once our lead optimization work has been completed." 
- BioAlliance Pharma
BioAlliance Pharma
BioAlliance Pharma is a privately held late stage biopharmaceutical company focused on drug resistance through development and commercialization of innovative therapeutics targeting markets in cancer, HIV, severe infections and supportive care. The company has two broad proprietary drug delivery systems represented by the Lauriad(R) adhesive technology and the Transdrug(R) nanoparticle technology that provide multiple product opportunities. Together with a New Chemical Entities program focused on development of new drugs in oncology and HIV, the company is able to address worldwide markets in the EU, US, and Asia.
The company's lead product within its adhesive technology program, the miconazole Lauriad(R) 50 mg Bioadhesive Buccal Tablet, is being investigated in two recently completed Phase III trials in Europe for treatment of oropharyngeal candidiasis in cancer and HIV patients. A pivotal Phase III trial in the same indication is planned for the U.S. later this year. A Phase I/II trial in hepatocellular carcinoma utilizing the company's doxorubicin Transdrug(R) nanoparticle delivery technology is ongoing in Europe, where it has been granted an orphan medicinal product designation by the EMEA.
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