Pro-drug peptide with improved pharmaceutical properties

Abstract

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.

What is claimed is: 
     
         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; 
 Z is a sequence of n amino acids, which is cleaved in vivo releasing pep; and 
 n is an integer ≥2. 
   
     
     
         2 . The pro-drug peptide of  claim 2 , wherein the Z has the following structure: (Glu-Pro) m  or (Lys-Pro) X , wherein X is an integer ≥1. 
     
     
         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-(Lys) m , 8-amino-3,6-dioxaoctanoic acid (8Ado), 8Ado-8Ado-(Lys) m , (Lys) m , or (Pro-Lys) m , wherein m is an integer from 0-10. 
     
     
         9 . The pro-drug peptide of  claim 2 , wherein at least two Lys of Z are functionalized with a soluble compound or moiety comprising: Ado, Ado-Ado-(Lys) m , 8Ado, 8Ado-8Ado-(Lys) m , (Lys) m , or (Pro-Lys) m . wherein m is an integer from 0-10. 
     
     
         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 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 comprises ≥2 amino acids that are cleaved in vivo releasing the peptide or peptidomimetic.   
     
     
         15 . The method of  claim 14 , wherein:
 the pro-drug portion has the following structure: (Glu-Pro) m  or (Lys-Pro) X , wherein X is ≥1;   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-(Lys) m , 8-amino-3,6-dioxaoctanoic acid (8Ado), 8Ado-8Ado-(Lys) m , (Lys) m , or (Pro-Lys) m . wherein m is an integer from 0-10;   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 15 , wherein at least the first Lys of the pro-drug portion is functionalized with a soluble compound. 
     
     
         17 . The method of  claim 15 , wherein at least two Lys of the pro-drug portion are functionalized with the soluble compound. 
     
     
         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. 
     
     
         19 . The method of  claim 16 , wherein the soluble compound 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-(Lys) m , 8Ado, 8Ado-8Ado-(Lys) m , (Lys) m , or (Pro-Lys) m , wherein m is an integer from 0-10.