Study backs integrase as novel drug target

Related tags Hiv Antiretroviral drug Hiv infection

A new family of drugs specifically designed to inhibit nuclear
import of integrase, blocking viral replication of human
immunodeficiency virus type 1 (HIV-1) infected cells suggests an
approach that could be effective against drug resistant strains of
HIV-1 which are rapidly emerging.

The inhibitor family, Styrylquinolines (SQ's), is being developed by Bioalliance Pharma, a biopharmaceutical company which focuses on the field of drug resistance.

Drug-resistant strains of human immunodeficiency virus type 1 (HIV-1) have arisen through the use of HIV-1 inhibitors such as reverse transcriptase and protease inhibitors.

Although the introduction of antiviral drugs has improved life expectancy around 270,000 US patients resistant to at least one class of HIV drug. Around 50,000 have developed resistance to all three currently available drug classes.

In addition, up to 20 per cent of new infections now involve the transmission of resistant virus, meaning new classes of antiviral drugs (especially against novel targets) will provide the only hope of treatment for an increasing number of patients.

For cell infection to take place, retroviral integration has to occur. This is the process that stably inserts the DNA copy of the viral genomic RNA into the host cell genome. The process is catalysed by the HIV integrase enzyme.

Since integrase has no direct cellular counterpart, it represents an attractive target for the treatment of HIV infection and supports the introduction of integrase inhibitors as a weapon against drug resistant viral strains.

"By demonstrating the inhibiting role of SQs in the nuclear import of viral integrase, it also pointing towards SQs as a tool for the identification of the elusive integrase import factor,"​ said Catherine Dargemont, lead investigator for the study.

Recent World Health Organisation statistics reveal HIV has become the fourth largest cause of death globally. There are an estimated 40 million HIV sufferers worldwide, with around 900,000 in the US and 600,000 in Western Europe. HIV represents a significant health problem in the western world. In the US, 300,000-400,000 patients receive treatment while the remaining patients either receives no treatment or are unaware they are infected with HIV.

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 optimization stage

The study appears in the latest edition of Molecular Pharmacology​ (Vol. 66, No. 4: 783-788, 2004).

Related topics Preclinical Research Ingredients

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