Amy I Evans

US Patent:

20030109675, Jun 12, 2003

Filed:

Oct 31, 2002

Appl. No.:

10/284252

Inventors:

C. Jones - Corvallis OR, US
Paul Dexter - Corvallis OR, US
Amy Evans - West Linn OR, US
Dennis Hruby - Albany OR, US

International Classification:

C07K001/00
C07K014/00
C07K017/00

US Classification:

530/350000

Abstract:

The DegP protease is essential for clearance of denatured or aggregated proteins from the periplasmic space in bacteria. The present invention relates to novel methods for treatment and/or prophylaxis of diseases caused by pilus-forming bacteria by modulating DegP protease activity. Also disclosed is the identification of DegP cleavage sites on PapA pilin subunit and methods for identifying substances which modulate DegP activity. The present invention further provides for polypeptides identified which are cleavable substrates for DegP. The present invention provides for the identification of a polypeptide which enhances DegP protease activity. The current invention facilitates the development of a novel class of anti-infectives targeting DegP protease.

US Patent:

6306619, Oct 23, 2001

Filed:

Jun 29, 2000

Appl. No.:

9/605858

Inventors:

Hal C. Jones - Corvallis OR
Christopher Liu - Cambridge MA
Scott J. Hultgren - Town and Country MO
Dennis E. Hruby - Albany OR
Christine A. Franke - Albany OR
Amy K. Evans - West Linn OR

Assignee:

Washington University - St. Louis MO
Siga Pharmaceuticals - New York NY

International Classification:

C12Q 137

US Classification:

435 23

Abstract:

The DegP (HtrA) protease is a multifunctional protein essential for the removal of misfolded and aggregated proteins in the periplasm. The present invention provides an assay for inhibitors of DegP activity, comprising mixing a suspected inhibitor of DegP activity with DegP and a suitable substrate (preferably a native substrate of DegP such as PapA) and detecting changes in DegP activity. DegP has been shown to be essential for virulence in several Gram negative pathogens. Only three natural targets for DegP have been described: colicin A lysis protein (Cal), pilin subunits (K88, K99, Pap) and recently HMW1 and HMW2 from Hemophilus influenzae. In vitro, DegP has shown weak protease activity on casein and several other non-native substrates. The present inventors have identified the major pilin subunit of the Pap pilus, PapA, as a native DegP substrate and demonstrated binding and proteolysis of this substrate in vitro. Using an NH. sub.