Oxyntomodulin analogs and methods of making and using same
Provided are oxyntomodulin analogs. The peptide analogs have at least two cysteines. The two cysteines are separated by six amino acids such that they can be crosslinked using suitable crosslinking moieties. The crosslinked peptides have long half-lives and/or efficacy. For example, peptide analog compositions are used for inducing weight loss and/or reducing blood glucose levels.
1. A crosslinked peptide having the following sequence:
HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA (SEQ ID NO:1), or a variant thereof having at least 65% homology with SEQ ID NO:1,
wherein a first amino acid at position i and a second amino acid at position i+7 are replaced independently by L-cysteine or D-cysteine,
i can be at any position from and including number 7 to number 30,
the crosslinked peptide is crosslinked with a crosslinking moiety between the cysteines at i and i+7 of the same peptide molecule, and
the crosslinking moiety is selected from the group consisting of:
wherein R at each occurrence on the crosslinking moiety is independently an H, a polyethylene glycol (PEG) group, a lipid group, or a PEG spacer moiety functionalized with a fatty diacid group.
2. The crosslinked peptide of claim 1 , wherein i is at position number 17 or number 21.
3. The crosslinked peptide of claim 1 , wherein the serine at position 2 is D-serine.
4. The crosslinked peptide of claim 1 , wherein the peptide is conjugated with at least one polyethylene glycol group and/or at least one lipid group.
5. The crosslinked peptide of claim 1 , wherein the amino acids at positions i+2 to i+6 have a sequence selected from the group consisting of:
RAQDFV (SEQ ID NO:3), AAKEFI (SEQ ID NO:4), AVRLFI (SEQ ID NO:5), and a sequence having at least 80% homology with SEQ ID NO:3, SEQ ID NO:4, or SEQ ID NO:5.
6. The crosslinked peptide of claim 1 , wherein the peptide has the following structure:
HsQGTFTSDYSKYLDECAAKEFICWLMNTKRNRNNIA (SEQ ID NO:11).
7. The crosslinked peptide of claim 6 , wherein the crosslinking moiety is selected from the group consisting of:
8. The crosslinked peptide of claim 7 , wherein R at each occurrence on the crosslinking moiety is an H.
9. A fusion protein comprising a crosslinked peptide of claim 1 , a peptide spacer, and a protein.
10. A composition comprising one or more crosslinked peptide of claim 1 and/or one or more fusion protein of claim 9 and a pharmaceutically acceptable carrier.
11. A method of lowering blood glucose level in an individual in need of treatment comprising administering a composition of claim 10 to the individual,
wherein the administration results in a lowered blood glucose level.
12. A method of inducing weight loss of an individual in need of treatment comprising administering a composition of claim 10 to the individual,
wherein the administration results in a lowered blood glucose level.