PAC1 receptor agonists (MAXCAPs) and uses thereof

Patent metadata

Field	Value
Publication number	US-12049486-B2
Application number	US-202117510090-A
Country	US
Kind code	B2
Filing date	Oct 25, 2021
Priority date	Jan 5, 2017
Publication date	Jul 30, 2024
Grant date	Jul 30, 2024

Abstract

In certain embodiments novel PAC1 receptor agonists are provided wherein the agonists comprise a targeting sequence that binds to the PAC1 receptor and said targeting sequence is attached to an amino acid sequence comprising a fragment of the maxadilan amino acid sequence, wherein the targeting sequence comprises a full-length 38 amino acid PACAP peptide or an N-terminus fragment thereof containing the amino acid sequence HSDGIF, wherein said targeting sequence optionally comprises an amino acid insertion between residues 11 and 12 of said PACAP peptide or fragment thereof; and the fragment of the maxadilan amino acid sequence comprises a fragment of the maxadilan sequence effective to activate PAC1 signaling.

First claim

What is claimed is:

1. A PAC1 receptor agonist, said agonist comprising:
a targeting sequence that binds to the PAC1 receptor attached to a peptide that activates PAC1 signaling, wherein:
said targeting sequence comprises a maxadilan peptide or fragment thereof effective to bind a PAC1 receptor; and
said peptide that activates PAC1 signaling comprises PACAP 1-38 or a fragment thereof, effective to activate PAC1 signaling, wherein:
said peptide that activates PAC1 signaling comprises an R to A mutation at residue 12 of said PACAP 1-38 ; or
said peptide that activates PAC1 signaling comprises an R to K mutation at residue 12 of said PACAP 1-38 ; or
said peptide that activates PAC1 signaling comprises a K to A mutation at residue 15 of said PACAP 1-38 .

2. The PAC1 receptor agonist of claim 1 , wherein the amino acid sequence of said peptide that activates PAC1 signaling consists of an amino acid sequence selected from the group consisting of HSDGIFTDSYSRYRKA (SEQ ID NO: 119),

(SEQ ID NO: 123)

HSDGIFTDSYSA, 

and

(SEQ ID NO: 124)

HSDGIFTDSYSK

3. The PAC1 receptor agonist of claim 1 , wherein said PAC1 receptor agonist, when administered to a mammal, is effective to downregulate appetite, reduce body weight, and/or slow the progression of NAFLD and/or NASH.

4. The PAC1 receptor agonist of claim 1 , wherein the amino acid sequence of said targeting sequence consists of an amino acid sequence selected from the group consisting of

(SEQ ID NO: 26)

MKQILLISLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSN

VLQTSVQTTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 27)

KQILLISLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNV

LQTSVQTTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 28)

QILLISLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVL

QTSVQTTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 29)

ILLISLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQ

TSVQTTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 30)

LLISLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQT

SVQTTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 31)

LISLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTS

VQTTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 32)

ISLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSV

QTTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 33)

SLVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQ

TTATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 34)

LVVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQT

TATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 35)

VVVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTT

ATFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 36)

VVLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTTA

TFTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 37)

VLAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTTAT

FTSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 38)

LAVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTTATF

TSMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 39)

AVFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTTATFT

SMDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 40)

VFAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTTATFTS

MDTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 41)

FAFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTTATFTSM

DTSQLPGNSVFKECMKQKKKEFSSGK,

(SEQ ID NO: 42)

AFNVAEGCDATCQFRKAIDDCQKQAHHSNVLQTSVQTTATFTSMD

Assignees

• Univ California
• The Us Gov Represented By The Department Of Veterans Affairs

Inventors

• Pisegna Joseph R
• Germano Patrizia M
• Vu John P

Classifications

• C07K2319/00

  Fusion polypeptide · CPC title

• C07K14/43577

  from flies · CPC title

• A61K38/2278

  Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin) · CPC title

• 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

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title