Small Molecule Allosteric Inhibitors of HIV Integrase

FCCC Ref. No. 425-MA


Small Molecule Allosteric Inhibitors of HIV Integrase (FCCC Ref. No. 425-MA) HIV-1 Integrase is the retroviral enzyme that inserts reverse transcribed viral DNA into the host genome and is a validated antiviral target. FDA approved drugs that inhibits HIV Integrase are available to treat patients and they work by targeting the active site. However, it is well documented that the virus has become resistant to these therapies. Researchers at the Fox Chase Cancer Center have identified unique compounds that inhibit Integrase activity by an alternative strategy to targeting functional integrase multimerization. These allosteric inhibitors can be new HIV therapies to viruses that have built resistance to approved drugs.

Summary of Invention

For HIV Integrase to function, at least 4 subunits assemble to form multimers that direct a coordinated insertion of two viral DNA ends into the host DNA (concerted integration). However, a partial defective reaction is also possible when one viral end is inserted (single end integration), and this reaction likely reflects impaired Integrase multimerization. The team at Fox Chase first developed a unique FRET based assay to a 384 well high throughput platform that can monitor the formation of Integrase multimers. This assay allowed the team to screen a 50,000-compound library and successfully identify 3 classes of small molecule inhibitors.

Class I: These hit compounds based on the toxoflavin scaffold and they have been shown to inhibit both single end joining and insertion reactions of Integrase.

Class II: The second class of compounds are hits that are nitro-benzofurazan derivatives and these compounds have the unique property of stimulating single end joining, while specifically inhibiting concerted integration. This suggest that class II compounds affect multimerization at a specific interface that is required for concerted activity.

Class III: A third class of more complex molecules uses a pyridopyrimidinone scaffold, and these inhibit both catalytic activities as is seen for the Class I scaffold.

Patent Status: Patent pending

For Licensing/Partnering information, please contact:
Inna Khartchenko, MS, MBA
Director, Technology Transfer
[email protected]