Bioalliance has announced results that clearly demonstrate its family of 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.
HIV resistance is fast becoming one of the most serious issues the industry has ever had to face. New strains of the virus have rendered most current AIDS treatments ineffective. Patients with a high degree of some drug resistance can usually find a second or third line drug therapy regimen for effective treatment.
However, strains of three-class antiretroviral-resistant HIV, or 3-DCR HIV have been discovered that do not respond to three classes of anti-retroviral medication, and also appear to shorten the interval between HIV infection and the onset of AIDS.
BioAlliance's lead SQL compound BA011FZ041, has previously shown in a study, published in the Journal of Virology, (Vol. 78, No. 11: 5728-5736, 2004) that integrase targeting molecules may act prior to integration and affect the accumulation of DNA during reverse transcription.
In addition, the research team from which came from the Ecole Normale Supérieure de Cachan, as well as BioAlliance Pharma, has also shown in a study (Molecular Pharmacology, Vol. 66, No. 4: 783-788, 2004) that SQLs specifically and efficiently inhibit nuclear import of integrase. More significantly, 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 potentialweapon in the fight against drug resistant viral strains.
"Synergy was observed with all three compounds, a result which is consistent with independent mechanisms of inhibition, said Jean-François Mouscadet, research director at the Laboratory for Biotechnology and Applied Pharmacology, Ecole Normale Supérieure de Cachan, France, and lead investigator for the study.
"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," he added.
The study confirms the potential of styrylquinolines as a promising route to the development of integrase inhibitors, By demonstrating the inhibiting role of SQLs in the nuclear import of viral integrase, it also pointing towards SQLs as a tool for the identification of the elusive integrase import factor.
Dominique Costantini, president and CEO of BioAlliance Pharma said: "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 optimisation work has been completed."
Currently there is a need for novel drugs with improved side-effect profile and/or easier administration. Present HIV drugs have serious side effects, which, for some patients, are intolerable. The complicated dosing regimen of certain drug combinations and the large pill number impose burdens on HIV patients. An attempt to solve these difficulties has led to pills such as Trizivir, containing three separate nucleoside reverse transcriptase inhibitors (NRTIs) in a single tablet.
Avexa is targeting the HIV integrase for which there is no inhibitor currently on the market. Given the success of drugs that inhibit the two other HIV enzymes, reverse transcriptase (RT) and protease (PR), there is every reason to believe that early entrants in the new class of integrase inhibitors will achieve significant sales.
Merck are presently conducting research of an integrase inhibitor, provisionally titled L870810. The active compound 1,6 napthridine carboxamide HIV integrase inhibitor is currently in Phase II of development. Likewise, Procyon's drug PL-2500, composed of Pryidoxal 1-5- Phosphate derivatives and Sunesis' monophores compound are currently at the lead optimisation stage