Bristol-myers Squibb Compnay

Richard J Colonno

Joel Charles Barrish

Mark R Krystal

Michael G Fakes

Christopher W Cianci

Omar L Sprockel

Thomas D Chung

Pin-Fang M Lin

Abizer Harianawala

Moira Hagen

Divyakant Desai

Novel capped oligonucleotides useful in treatment of influenza infection. A synthetically derived 67-nucleotide RNA substrate, containing a �.sup.32 P! labeled cap-1 structure was used to analyze parameters of influenza virus endonuclease activity. This substrate was specifically cleaved by the influenza virus polymerase to yield a single capped 11-nucleotide fragment capable of directly priming transcription. An analysis of systematic truncations of this RNA substrate in cleavage, elongation, and binding reactions demonstrated that the minimum chain length required for cleavage was one nucleotide past the cleavage site. In contrast, the minimum chain length required for priming activity was found to be 9 nucleotides, while a chain length of at least 4 nucleotides was required for efficient binding. Based on these chain length requirements, the present inventors show that a pool of capped oligonucleotides--too short to prime transcription but long enough to bind with high affinity to the viral polymerase--are potent inhibitors of cap-dependent in vitro transcription.

Capped nucleic acid oligomers that inhibit cap-dependent transcription

Combinations of certain HIV-1 protease inhibitors are provided which effectively inhibit the HIV-1 protease enzyme while eliminating or substantially reducing the viral cross-resistance seen with use of individual HIV-1 protease inhibitors. Such combinations are useful in the treatment of diseases associated with the AIDS virus.

HIV protease inhibitor combinations

Growing community of inventors

Buckingham, PA, United States of America

Richard J Colonno