'Double-drugs' - A new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker

We designed and synthesized a new series of prodrug-type anti-HIV agents co nsisting of a peptidomimetic HIV protease inhibitor conjugated with a nucle oside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoin the two di fferent classes of inhibitors have been investigated. Conjugates using a su ccinyl amino acid linker were shown to release the parent components via th e spontaneous imide formation at a faster rate compared to conjugates using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Herein, we report a new 'double-dru g' 4b (KNI-1039) with a glutarylglycine linker, which exhibited extremely p otent anti-HIV activity compared with that of the individual components. (C ) 2000 Elsevier Science Ltd. All rights reserved.