Boehringer Ingelheim (canada) Ltd.

Boehringer Ingelheim International Gmbh

Boehringer Ingelheim Gmbh

Peter White

Christiane Yoakim

Nathalie Goudreau

Jeffrey O'Meara

William W Ogilvie

Jean Rancourt

Youla S Tsantrizos

Dale R Cameron

Anne-Marie Faucher

Yong Wang

Jacques Archambault

Bruno Hache

Bruno Hach&eacute;

A compound of formula (I) or its enantiomers or diastereoisomers thereof: wherein: A,; X, W, R, Y; R; and Rare as defined herein. The compounds of the invention may be used as inhibitors of the papilloma virus E1-E2-DNA complex. The invention further provides a method of treating or preventing human papilloma virus infection.

Inhibitors of papilloma virus

The use of a compound of formula (II): or its enantiomers or diastereoisomers thereof, or salts or pharmaceutically-acceptable esters thereof, in the treatment or prevention of a papilloma virus infection, particularly human papilloma virus in a mammal, wherein R; X; X; X; R; R; W; Z; Y; T; and Rare defined herein. The present invention also provides novel compounds, pharmaceutical compositions and methods for using these compounds and compositions in the treatment or prevention of papilloma virus infection. More particularly, the present invention provides compounds, compositions and methods for inhibiting papilloma virus DNA replication by interfering with the E1-E2 protein-protein interaction essential for viral DNA replication.

A compound of formula (I) or its enantiomers or diastereoisomers thereof: wherein: A, X, W, R, Y; R; and Rare as defined herein. The compounds of the invention may be used as inhibitors of the papilloma virus E1-E2-DNA complex. The invention further provides a method of treating or preventing human papilloma virus infection.

A crystallizable composition, comprising an human papillomavirus (HPV-11) E2 transactivation domain (TAD)-like polypeptide of SEQ ID NO. 2 complexed with an inhibitor L (sodium (2R,3R,4S,5R)-5-(3,4-dichlorophenyl)-5'-methyl-1&#x2032;,3&#x2032;-dioxo-4-({[4-(1,2,3-thiadiazol-4-yl)phenyl]amino}carbonyl)-1&#x2032;,3&#x2032;,4,5-tetrahydro-3H-spiro[furan-2,2&#x2032;-indene]-3-carboxylate). The invention also provides a method for producing the crystallized HPV E2 TAD-inhibitor complex (HPV E2 TAD-L) comprising: a) mixing purified HPV E2 TAD, contained in a purification buffer, with solublized inhibitor L to generate a complex solution containing the HPV E2 TAD-L complex; and b) crystallizing the complex from a) in a crystallization buffer. The invention also provides a method for producing crystallized apo HPV E2 TAD, comprising: a) mixing apo HPV E2 TAD, contained in a purification buffer, with a crystallization buffer. X-ray crystal structure coordinates the HPV E2 TAD-L complex, are also provided, which define an inhibitor binding pocket. The inhibitor binding pocket is useful for screening potential small molecule inhibitors that bind to the pocket that may be inhibitors of papillomavirus infection.

Method of identifying potential inhibitors of human papillomavirus protein E2 using x-ray atomic coordinates

The present invention uses the principle that phosphomolybdate binds to hydrophobic surfaces to isolate the phosphomolybdate complex from other phosphate-containing molecules and further uses the SPA concept to bring a radiolabeled phosphomolybdate complex in close contact with a scintillant for measurement by scintillation counting. Generally, the present invention provides an assay for detecting and measuring the amount of orthophosphate (Pi) in an aqueous reaction mixture, wherein the amount of Pi released is separated from the reaction mixture by: adding a solution of molybdate to the reaction mixture to form a phosphomolybdate complex; and contacting the phosphomolybdate complex with a hydrophobic surface, wherein the surface is capable of being separated from the aqueous reaction mixture to allow measurement of the Pi. Particularly, this invention provides an assay for measuring the ATPase activity of enzymes, more particularly, the HPV E1 helicase.

Methods for determining ATPase activity and uses thereof

E2 displacement assay for identifying inhibitors of HPV

Atpase assay

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Montreal, Canada

Peter White