Merck + Co., Inc.

Sloan-kettering Institute for Cancer Research

Memorial Sloan Kettering Cancer Center

Merk & Co., Inc.

Yueming Li

Jules A Shafer

Ming-Tain Lai

Mohinder Sardana

Stephen F Brady

Victor M Garsky

James E Bruce

Xiaoting Tang

Stephen J Gardell

Elizabeth Chen-Dodson

Bruce D Dorsey

David A Scheinberg

Alan John Nadin

Daria Hazuda

Joseph George Neduvelil

Min Xu

Adam J Simon

Dennis C Dean

Ming-Chih Crouthamel

Sindy Noemi Escobar-Alvarez

Elizabeth Chen Dodson

Yehuda Goldgur

Xiao-Ping Shi

Lei Zhu

Guoxin Wu

Bruce Register

Christopher Chad Shelton

Qian Huang

Yuan Tian

Provided are methods of treating or preventing a neurodegenerative disease comprising administering to a subject having a neurodegenerative disease an effective amount of a compound of Formula I: where X, R, R, subscript m, subscript n and subscript v are as defined herein.

Methods for treating or preventing cancer and neurodegenerative diseases

Polypeptide substrates based on modifications or fragments of the various APP isoforms, assay methods based on the use of these substrates, and screening methods directed toward identifying inhibitors of &#x3b3;-secretase activity. The assay methods and the screening methods are adapted for use in high throughput multi-well plate assay apparatuses. In many embodiments the substrate polypeptides are labeled for ease of detection, and/or may bind specific ligands that themselves are labeled. Generally the labels promote high specificity as well as high sensitivity of detection. These features render the assay and screening methods that employ the labeled substrates especially suited for use in high throughput assay formats. This disclosure further identifies small polypeptides based on a subsequence motif of A&#x3b2; that are shown herein to be potent inhibitors of the activity of &#x3b3;-secretase.

&#x3b3;-Secretase substrates and methods of use

The present invention provides the three-dimensional structure of human mitochondrialpeptide deformylase (HsPDF) protein, and HsPDF complexed to a binding compound, such as a PDF inhibitor. This crystallographic information will aid in the identification and development of novel binding compounds of HsPDF and other PDF family members which have anti-bacterial, anti-viral, anti-parasitical, anti-inflammatory, and/or anti-cancer activity.

Method of inhibitor design and identification using a 3-D structure of human peptide deformylase

The present invention provides synthetic &#x3b2;-secretase peptide substrates useful in various assays for measuring &#x3b2;-secretase activity. Antibodies that recognize the synthetic substrates and uses of the antibodies in various assays are disclosed. The herein disclosed peptide substrates are hydrolyzed at rates substantially faster than the attendant Swedish mutant APP from which the substrate sequences are derived.

Beta-secretase substrates and uses thereof

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

Growing community of inventors

New York, NY, United States of America

Yueming Li