Pro-drug peptide with improved pharmaceutical properties
The present disclosure relates to a pro-drug peptide, or a salt thereof, having improvement for at least one biological property relative to a parent peptide or peptidomimetic, wherein the biological property is selected from the group consisting of therapeutic index, stability, solubility, toxicity, adsorption, and pre-systemic metabolism. The pro-drug peptide comprising the following structure: Z-pep, wherein: pep is the parent peptide or peptidomimetic; Z is a sequence of n amino acids, Z is cleaved in vivo releasing pep; n≥2 amino acids. The present disclosure also relates to methods of making and using the pro-drug peptide of the present disclosure. For example, the present disclosure describes a pro-drug peptide that may be used to prevent, treat, or ameliorate at least one symptom of hypoglycemia or a hypoglycemia-related disease or disorder.
1. A pro-drug peptide or salt thereof having improvement for at least one biological property relative to a parent peptide or peptidomimetic, wherein the biological property is selected from the group consisting of therapeutic index, stability, solubility, toxicity, adsorption, and pre-systemic metabolism, the pro-drug peptide comprising the following structure:
Z n -pep,
wherein:
pep is the parent peptide or peptidomimetic that is glucagon or an analog thereof; and
Z is attached to the n-terminus of pep and is cleaved in vivo releasing pep, wherein Z has the structure (Glu-Pro) X or (Lys-Pro) X , and X is an integer ≥1.
2. The pro-drug peptide of claim 1 , wherein the Z has the structure (Lys-Pro) X .
3. The pro-drug peptide of claim 1 , wherein the Z is selected from the group consisting of EP, KP, EPEP, KPKP, EPEPEP, and KPKPKP.
4. The pro-drug peptide of claim 2 , wherein at least the first Lys of Z is functionalized with a soluble compound or moiety.
5. The pro-drug peptide of claim 2 , wherein at least two Lys of Z are functionalized with the soluble compound or moiety.
6. The pro-drug peptide of claim 1 , wherein the Z comprises two amino acids, and the first amino acid is functionalized with a soluble compound or moiety.
7. The pro-drug peptide of claim 4 , wherein the soluble compound or moiety is hydrophilic.
8. The pro-drug peptide of claim 1 , wherein the first amino acid of Z is functionalized with a soluble compound or moiety comprising: 12-aminododecanoic acid (Ado), Ado-Ado, Ado-Ado-(Lys) m , 8-amino-3,6-dioxaoctanoic acid (8Ado), 8Ado-8Ado, 8Ado-8Ado-(Lys) m , (Lys) m -8Ado-8Ado, (Lys) m , or (Lys-Pro) m , wherein m is an integer from 1-10.
9. The pro-drug peptide of claim 1 , wherein at least two Lys of Z are functionalized with a soluble compound or moiety comprising: Ado, Ado-Ado, Ado-Ado-(Lys) m , 8Ado, 8Ado-8Ado, 8Ado-8Ado-(Lys) m , (Lys) m -8Ado-8Ado, (Lys) m , or (Lys-Pro) m , wherein m is an integer from 1-10.
10. The pro-drug peptide of claim 1 , wherein the c-terminus of the peptide is amine modified.
11. The pro-drug peptide of claim 1 , wherein the parent peptide or peptidomimetic has an amino acid sequence that is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO: 1 (HSQGTFTSDYSKYLDSRRAQDFVQWLMNT) and SEQ ID NO: 2 (HSQGTFTSDYSKYLDSRRAQDFVQWLLNT).
12. A pharmaceutical composition comprising: an effective amount of the pro-drug of claim 1 , and a pharmaceutically acceptable excipient or carrier.
13. A method of treating or preventing hypoglycemia or a hypoglycemia related disorder or disease, the method comprising: administering an effective amount of the pharmaceutical composition of claim 12 , wherein the pro-drug peptide is effective at treating or preventing hypoglycemia or the hypoglycemia related disorder or disease.
14. A method of preparing a pro-drug peptide or salt thereof having improvement for at least one biological property relative to a parent peptide or peptidomimetic, wherein the biological property is selected from the group consisting of therapeutic index, stability, solubility, toxicity, adsorption, and pre-systemic metabolism, the method comprising:
adding a pro-drug portion to the parent peptide or peptidomimetic,
wherein:
the pro-drug portion is cleaved in vivo releasing the peptide or peptidomimetic;
the pro-drug portion has the structure (Glu-Pro) X or (Lys-Pro) X ;
X is an integer ≥1; and
the parent peptide or peptidomimetic is glucagon or an analog thereof.
15. The method of claim 14 , wherein:
the pro-drug portion has the structure (Lys-Pro) X ;
the pro-drug portion is selected from the group consisting of EP, KP, EPEP, KPKP, EPEPEP, and KPKPKP;
the first amino acid of the pro-drug portion is functionalized with a soluble compound or moiety comprising: 12-aminododecanoic acid (Ado), Ado-Ado, Ado-Ado-(Lys) m , 8-amino-3,6-dioxaoctanoic acid (8Ado), 8Ado-8Ado, 8Ado-8Ado-(Lys) m , (Lys) m -8Ado-8Ado, (Lys) m , or (Lys-Pro) m , wherein m is an integer from 1-10;
the parent peptide or peptidomimetic has an amino acid sequence that is at least 85% identical to a sequence selected from the group consisting of SEQ ID NO: 1 (HSQGTFTSDYSKYLDSRRAQDFVQWLMNT) and SEQ ID NO: 2 (HSQGTFTSDYSKYLDSRRAQDFVQWLLNT);
the method further comprises amidating the c-terminus of the peptide or modifying the c-terminus of the protein with an amine; or
a combination thereof.
16. The method of claim 14 , wherein at least the first Lys of the pro-drug portion is functionalized with a soluble compound or moiety.
17. The method of claim 14 , wherein at least two Lys of the pro-drug portion are functionalized with the soluble compound or moiety.
18. The method of claim 14 , wherein the pro-drug portion comprises two amino acids, and the first amino acid is functionalized with a soluble compound or moiety.
19. The method of claim 16 , wherein the soluble compound or moiety is aqueously soluble.
20. The method of claim 15 , wherein at least two Lys of the pro-drug portion is functionalized with a soluble compound or moiety comprising: Ado, Ado-Ado, Ado-Ado-(Lys) m , 8Ado, 8Ado-8Ado, 8Ado-8Ado-(Lys) m , (Lys) m -8Ado-8Ado, (Lys) m , or (Lys-Pro) m , wherein m is an integer from 1-10.
21. The pro-drug peptide of claim 1 , wherein the Z is KP.
22. The pro-drug peptide of claim 21 , wherein the Lys of Z is functionalized with a soluble compound or moiety via an epsilon-N linkage.
23. The pro-drug peptide of claim 22 , wherein the soluble compound or moiety comprises: 12-aminododecanoic acid (Ado), Ado-Ado, Ado-Ado-(Lys) m , 8-amino-3,6-dioxaoctanoic acid (8Ado), 8Ado-8Ado, 8Ado-8Ado-(Lys) m , (Lys) m -8Ado-8Ado, (Lys) m , or (Lys-Pro) m , wherein m is an integer from 1-10.
24. The pro-drug peptide of claim 22 , wherein the soluble compound or moiety is KP.
25. The pro-drug peptide of claim 1 , wherein the parent peptide or peptidomimetic has an amino acid sequence that is at least 85% identical to the sequence of SEQ ID NO: 2 (HSQGTFTSDYSKYLDSRRAQDFVQWLMNT).
26. The pro-drug peptide of claim 25 , wherein Z is KP.
27. The pro-drug peptide of claim 26 , wherein the lysine of Z is functionalized with a soluble compound or moiety via an epsilon-N linkage.
28. The pro-drug peptide of claim 27 , wherein the soluble compound or moiety is (Lys-Pro) m , wherein m is 3.
29. The pro-drug peptide of claim 1 , wherein:
the prodrug has the structure:
K*PHSQGTFTSDYSKYLDSRRAQDFVQWLMNT KPKPKP; and
K* is represented by the structure: