NOVEL GENES RELATED TO GLUTAMINYL CYCLASE

• US 20100009337A1
• Filed: 07/02/2009
• Published: 01/14/2010
• Est. Priority Date: 09/21/2006
• Status: Active Grant

• Current Assignee: Probiodrug AG
• Original Assignee: Probiodrug AG
• Inventors: Demuth, Hans-Ulrich, Schilling, Stephan, Rahfeld, Jens-Ulrich, Cynis, Holger
• Granted Patent: US 8,129,160 B2
• Time in Patent Office: Days
• US Class Current: 435/4
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 233/54 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 233/61 with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
• CPC Class Codes: C07D 235/06 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C12N 9/104 : Aminoacyltransferases (2.3.2)

Abstract

Novel glutaminyl-peptide cyclotransferase-like proteins (QPCTLs), which are isoenzymes of glutaminyl cyclase (QC, EC 2.3.2.5), and to isolated nucleic acids coding for these isoenzymes, all of which are useful for the discovery of new therapeutic agents, for measuring cyclase activity, and for determining the inhibitory activity of compounds against these glutaminyl cyclase isoenzymes.

Claims

1. A method of screening for a compound capable of inhibiting an enzymatic activity, comprising:

incubating at least a first polypeptide and a suitable substrate for the at least a first polypeptide in the presence of at least one test compound or salt thereof;

measuring an enzymatic activity of the at least a first polypeptide;

comparing said activity with enzymatic activity determined in the absence of the at least one test compound or salt thereof; and

selecting a test compound that reduces the enzymatic activity of the at least a first polypeptide;

wherein the at least a first polypeptide comprises;

(a) an amino acid sequence selected from the group consisting of SEQ ID NO;

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

21, and SEQ ID NO;

22, or an amino acid sequence having at least about 90% sequence identity thereto and having glutaminyl cyclase activity;

(b) an amino acid sequence encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7, SEQ ID NO;

8, SEQ ID NO;

9, SEQ ID NO;

19, and SEQ ID NO;

20, or an alternative splice variant thereof;

or

(c) a fragment of (a) or (b) wherein said fragment is immunologically reactive and has glutaminyl cyclase activity; and

the at least a first polypeptide is optionally glycosylated.

2. The method of claim 1, wherein the at least a first polypeptide comprises an amino acid sequence having at least about 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO:

11, SEQ ID NO;

12, SEQ ID NO;

13, SEQ ID NO;

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

21, or SEQ ID NO;

22 and has glutaminyl cyclase activity.

3. The method of claim 1 wherein the enzymatic activity is glutaminyl cyclase activity.

4. The method of claim 3 comprising:

incubating a polypeptide comprising SEQ ID NO;

10 (wild type human glutaminyl cyclase) and a suitable substrate for wild type human glutaminyl cyclase in the presence of the at least one test compound or salt thereof;

measuring the glutaminyl cyclase activity of the polypeptide comprising SEQ ID NO;

10; and

selecting a test compound that reduces the glutaminyl cyclase activity of the at least one polypeptide of claim 10 but does not reduce the glutaminyl cyclase activity of the polypeptide comprising SEQ ID NO;

10.