Merck + Co., Inc.

Merck Sharp + Dohme Corp.

Merk & Co., Inc.

Merck Sharp & Dohme LLC

Ming-Tain Lai

Yueming Li

Daria Hazuda

Ming-Chih Crouthamel

Stephen J Gardell

Bruce D Dorsey

Stephen F Brady

Alan John Nadin

Jules A Shafer

Joseph George Neduvelil

Min Xu

Mohinder Sardana

Adam J Simon

Dennis C Dean

Elizabeth Chen Dodson

Xiao-Ping Shi

Guoxin Wu

Bruce Register

Qian Huang

The instant invention relates to a method for reducing the risk for development of anti-viral treatment resistance due to an HIV mutation in a human subject infected with HIV, comprising administering EFdA in combination with one or more anti-viral agents.

HIV drug combination for increasing barrier against resistance

The present invention provides compounds that are inhibitors of the proteolytic activity of the enzyme &#x3b2;-secretase, pharmaceutically acceptable salts of the compounds, pharmaceutical compositions comprising the compounds, processes for making the compounds, and methods of using the compounds to treat Alzheimers disease.

&#x3b2;-secretase inhibitors

Provided are methods of identifying inhibitors of &#x3b2;-secretase that employ modified &#x3b2;-secretase substrates. The modified &#x3b2;-secretase substrates have &#x3b2;-secretase cleavage sites that are altered from wild type. The amino acid sequences of the altered &#x3b2;-secretase cleavage sites contain different amino acids in at least one of the positions P2-P1-P1'-P2&#x2032; of the &#x3b2;-secretase cleavage site. Many of the modified &#x3b2;-secretase substrates are more efficient substrates for &#x3b2;-secretase than are corresponding substrates having wild-type sequences, that is, these modified substrates are more susceptible to enzymatic breakdown by &#x3b2;-secretase. Recombinant polynucleotide molecules encoding the modified &#x3b2;-secretase substrates are provided. Antibodies that recognize cleavage products of the modified &#x3b2;-secretase substrates are provided. Stable cell lines expressing the modified &#x3b2;-secretase substrates are provided. Transgenic animals expressing the modified &#x3b2;-secretase substrates are provided.

Assays using amyloid precursor proteins with modified &#x3b2;-secretase cleavage sites to monitor &#x3b2;-secretase activity

Gamma three protease is provided, a novel aspartyl class protease that is capable of taking part in the processing of amyloid precursor protein (APP) to A&#x3b2; peptide. Gamma three protease may be involved in the development and/or progression of Alzheimers disease. Methods of identifying inhibitors of gamma three protease, useful in the prevention or treatment of Alzheimers disease, are disclosed.

Gamma three protease

The present invention is directed to compounds and pharmaceutical compositions comprising the compounds which are inhibitors of the enzyme gamma secretase and which are useful in the treatment or prevention of diseases in which the beta-amyloid peptide is involved, such as Alzheimer's disease.

Investigational compounds

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Lansdale, PA, United States of America

Ming-Tain Lai