Pharmacological modulators of gabaa receptors and their use

Patent metadata

Field	Value
Publication number	US-2018009859-A1
Application number	US-201615544030-A
Country	US
Kind code	A1
Filing date	Jan 14, 2016
Priority date	Jan 15, 2015
Publication date	Jan 11, 2018
Grant date	—

Abstract

The present invention provides polypeptides and their variants and derivatives which modulate GABA A receptor function at nanomolar quantities by binding to the α+/β− subunit interface, as well as methods of making and using the same. The inventive peptides are useful for the study of neurological disease and function and can have therapeutic applications.

First claim

1 . (canceled)

2 . A polypeptide having GABA A modulating activity comprising the following amino acid sequence selected from the group consisting of:
a)

(SEQ ID NO: 1)

LTCKTCPFTTCPNSESCPGGQSICYQRKWEEHRGERIERRCVANCP

AFGSHDTSLLCCTRDNCN;

(SEQ ID NO: 2)

LTCKTCPFTTCPNSESCPGGQSICYQRKWEEHHGERIERRCVANCP

AFGSHDTSLLCCTRDNCN ;

(SEQ ID NO: 8)

Leu Thr Cys Lys Thr Cys Pro Phe Thr Thr Cys Pro

Asn Ser Glu Ser Cys Pro Gly Gly Gln Ser Ile Cys

Tyr Gln Arg Lys Trp Glu Glu His Arg Gly Glu Arg

Ile Glu Arg Arg Cys Val Ala Asn Cys Pro Ala Phe

Gly Ser His Asp Thr Leu Leu Cys Cys Thr Arg Asp

Asn Cys Asn ;

(SEQ ID NO: 9)

Met Lys Cys Leu Ile Cys Pro Phe Thr Thr Cys Ser

Gln Ser Glu Ser Cys Pro Gly Gly Gln Ser Ile Cys

Phe Gln Arg Lys Phe Asp Asp Arg His Gly Asp Arg

Ile Glu Arg Gly Cys Ala Val Thr Cys Pro Pro Phe

Gly Ser His Asp Thr Ile Phe Cys Cys Ser Thr Asn

Asp Cys Asn ;

(SEQ ID NO: 10)

Ile Glu Cys His Asn Cys Pro Phe Thr Thr Cys Gly

Asn Ser Glu Ser Cys Pro Gly Gly Gln Ser Ile Cys

Val Gln Arg Lys Leu Glu Glu Lys Lys Gly Glu Arg

Ile Glu Arg Ser Cys Thr Asp Gly Cys Pro Gly Phe

Gly Ser His Asp Thr Val Glu Cys Cys Arg Ile Ala

Arg Cys Asn ;

(SEQ ID NO: 11)

Arg Gln Cys Tyr Thr Cys Pro Phe Thr Thr Cys His

Asn Ser Glu Ser Cys Pro Gly Gly Gln Ser Ile Cys

Tyr Gln Arg Lys Tyr Glu Glu His Arg Gly Glu Arg

Ile Glu Arg Lys Cys Ser Leu Ser Cys Pro Ser Phe

Gly Ser His Asp Thr Leu Leu Cys Cys Ala Arg Pro

Lys Cys Asn ;

(SEQ ID NO: 12)

Phe Arg Cys Phe Arg Cys Pro Phe Thr Thr Cys Asn

Asn Ser Glu Ser Cys Pro Gly Gly Gln Ser Ile Cys

Tyr Gln Arg Lys Trp Glu Glu His Arg Gly Glu Arg

Ile Glu Arg Arg Cys Val Ala Asn Cys Pro Ala Phe

Gly Ser His Asp Thr Leu Leu Cys Cys Lys Arg Gl u

Glu Cys Asn ;

(SEQ ID NO: 13)

Leu Ser Cys Asn Thr Cys Pro Phe Thr Thr Cys Gln

Asn Ser Glu Ser Cys Pro Gly Gly Gln Ser Ile Cys

Tyr Gln Arg Lys Trp Glu Glu His Arg Gly Glu Arg

Ile Glu Arg Arg Cys Val Ala Asn Cys Pro Ala Phe

Gly Ser His Asp Thr Leu Leu Cys Cys Thr Arg Asp

Asn Cys Asn ;

and

(SEQ ID NO: 14)

Leu Leu Cys Lys Thr Cys Pro Phe Thr Thr Cys Pro

Asn Ser Glu Ser Cys Pro Gly Gly Gln Ser Ile Cys

Tyr Gln Arg Lys Trp Glu Glu His Arg Gly Glu Arg

Ile Glu Arg Arg Cys Val Ala Asn Cys Pro Ala Phe

Gly Ser His Asp Thr Leu Leu Cys Cys Thr Arg Asp

Asn Cys Asn ;

Assignees

• Univ Johns Hopkins

Inventors

• Bosmans Frank
• Bougis Pierre Edouard

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K49/0056

  Peptides, proteins, polyamino acids · CPC title

• C07K14/46

  from vertebrates · CPC title

• C07K14/4702 Primary

  Regulators; Modulating activity · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title