Researchers at Oxford University’s Sir William Dunn School of Pathology in the UK develop a novel HTS for identifying antiretroviral (HIV) agents/drugs that inhibit HIV infectivity.
Isis Innovation Ltd seeks potential partners.
The Oxford researchers have identified a panel of aptamers that bind to functionally conserved sites on the gp120 and neutralise virus infectivity. These functionally conserved sites on gp120 are glycosylation independent and include the cell surface receptor binding sites on the clinically predominant macrophage-tropic HIV-1 strains.
While anti-virals currently prolong the quality of life for many HIV-1 positive individuals they do not prevent the virus from infecting new cells. As agents in use mostly target intracellular replication, natural mutation of the virus has led to the development of drug resistant strains.
Candidate vaccines based on the HIV-1 surface glycoprotein (gp120) with the ability to neutralise HIV-1 primary isolates have generally failed. This has driven a research effort to discover novel antiretrovirals with different characteristics from those currently in use. Aptamer-gp120 interactions can be exploited in a HTS to identify small molecule inhibitors, which would be lead candidates for anti-HIV infectivity agents.
A logical target for anti-HIV therapy is the initial infection of the cell through entry of the virus. This feature, plus its cellular tropism, and the pathogenesis of AIDS, are largely determined by gp120 and its interactions. Strains of HIV that depend on the chemokine co-receptor 5 are preferentially transmitted from host to host, dominate the early, asymptomatic, stage of infection, and are sufficient to cause AIDS.
A limited number of new anti-virals that inhibit infectivity are close to market or in development. However, the infectivity assays are very complex and are not particularly amenable to high throughput screening (HTS) systems to identify potent new lead compounds.
At Oxford, researchers identified a panel of aptamers (nucleic acid ligands) that bind to functionally conserved sites on the gp120 and neutralise virus infectivity. These functionally conserved sites on gp120 are glycosylation independent and include the cell surface receptor binding sites on the clinically predominant macrophage-tropic HIV-1 strains.
Using this discovery, they have designed a surrogate assay, which enables compounds to be screened for anti-infectivity characteristics and identified.
The aptamer-gp120 interactions can be exploited in a HTS to identify small molecule inhibitors, which would be lead candidates for anti-HIV infectivity agents.
Isis Innovation, Oxford University’s technology transfer company, has filed a patent on this exciting development in anti-retroviral drug discovery and welcomes contact from potential commercial partners.
Keywords : Oxford University UK Sir Willim Dunn School of Pathology Isis Innovation Ltd Antiretroviral HIV agent Virus infectivity neutralisation Lead compound identification HTS
