Adrenocorticotropic hormone analogs and related methods

Abstract

ACTH analog compounds of the present invention include compounds comprising an ACTH peptide sequence with one or more structural modifications that can have one or more of the following preferred ACTH analog biological functions: (1) reduction of corticosteroid secretion by adrenal membrane in the presence of the ACTH analog compared to unmodified ACTH, (2) reduction of corticosteroid secretion by adrenal membrane in the presence of endogenous ACTH and (3) increased MC-2R binding affinity with reduced activation of the MC-2R receptor compared to unmodified ACTH binding to the MC-2R melanocortin. The ACTH analog compounds of the present invention are therefore useful for treatment or prevention of diseases and disorders related to ACTH, ACTH receptors or corticosteroid secretion, such as premature labor and Cushing's Disease.

1 - 21 . (canceled)  
     
     
         22 . A composition comprising an isolated ACTH analog peptide, the ACTH analog peptide comprising the peptide of SEQ ID NO:2 with at least one of the following amino acid substitutions: 
 a. the substitution of the Pro residue at position 19 of SEQ ID NO:2 with the amino acid Trp; or    b. one or more amino acid substitutions of residues selected from amino acid residues 16 to 18 of SEQ ID NO:2, such that 
 i. the amino acid residues 16, 17 and 18 of the ACTH analog do not include any two adjacent amino acid residues selected from the group consisting of: Lys and Arg; and  
 ii. the one or more amino acid residues substituted at position 16, 17 or 18 of SEQ ID NO:2 are selected from the group consisting of: Lys, Arg, Ala, Gly, Val, Leu, Ile, an amino acid analog comprising an alkyl side chain, Gln, Asn, Glu, and Asp.  
   
     
     
         23 . The composition of claim  1 , wherein the ACTH analog peptide comprises at least one Ala and at least one Arg residue substituted at any two of the amino acid positions 15, 16, 17 or 18 of SEQ ID NO:2.  
     
     
         24 . The composition of claim  1 , wherein the ACTH analog consists essentially of the sequence of SEQ ID NO:2 with the following amino acid substitutions: 
 a. the Pro residue at position 19 of SEQ ID NO:2 is substituted with the amino acid Trp;    b. the amino acid at position 15 of SEQ ID NO:2 is-selected from the group consisting of: Lys, Ala and Gln; and    c. the ACTH analog peptide comprises one or more amino acid substitutions of residues selected from amino acid residues 16 to 18 of SEQ ID NO:2, such that the amino acid residues 16, 17 and 18 of the ACTH analog do not include any two adjacent amino acid residues selected from the group consisting of: Lys and Arg.    
     
     
         25 . The composition of claim  1 , wherein the ACTH analog peptide includes the amino acid sequence -His 6 -Phe 7 -Arg 8 -Trp 9 - at amino acid residues 6-9.  
     
     
         26 . The composition of claim  1 , where the ACTH analog peptide comprises an amino acid sequence selected from the group consisting of: 
 a. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Arg-Ala-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    b. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Ala 15 -Lys-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    c. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Ala-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    d. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Ala-Arg-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    e. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Gln 15 -Lys-Gln-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    f. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Ala 15 -Ala-Ala-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    g. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Arg-Ala-Ala-Trp-Val 20 -Lys-Val-Tyr-Pro-;    h. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Ala 15 -Lys-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    i. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Ala-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    j. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Ala-Arg-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    k. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Gln 15 -Lys-Gln-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    l. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Arg-Ala-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-; and    m. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Lys-Arg-Arg-Pro-Ala 20 -Ala-Ala-Ala-Ala-.    
     
     
         27 . The composition of claim  1 , wherein the ACTH analog peptide performs at least one of the following functions: 
 a. administration of the ACTH analog peptide in an in vivo Serum Corticosteroid Inhibition Assay reduces ACTH-induced corticosteroid secretion by at least a 10%;    b. the ACTH analog peptide binds to adrenal membrane and displaces a peptide of SEQ ID NO:2 from adrenal membrane, where the peptide binding is measured by an in vitro Serum-free Adrenal Competitive Binding Assay;    c. the ACTH analog peptide binds to the MC-2R adrenal membrane with at least a 2-fold greater affinity than the peptide of SEQ ID NO:2; and    d. the ACTH analog peptide reduces the ACTH induced production of corticosterone by adrenal membrane in an in vitro Serum-free Adrenal Inhibition Assay.    
     
     
         28 . A composition comprising an isolated ACTH analog peptide, the ACTH analog peptide comprising the peptide of SEQ ID NO:2 with at least one amino acid substitution or deletion, wherein the ACTH analog peptide performs at least one of the following functions: 
 a. administration of the ACTH analog peptide in an in vivo Serum Corticosteroid Inhibition Assay reduces ACTH-induced corticosteroid secretion by at least a 10%;    b. the ACTH analog peptide binds to adrenal membrane and displaces a peptide of SEQ ID NO:2 from adrenal membrane, where the peptide binding is measured by an in vitro Serum-free Adrenal Competitive Binding Assay;    c. the ACTH analog peptide binds to the MC-2R adrenal membrane with at least a 2-fold greater affinity than the peptide of SEQ ID NO:2; and    d. the ACTH analog peptide reduces the ACTH induced production of corticosterone by adrenal membrane in an in vitro Serum-free Adrenal Inhibition Assay.    
     
     
         29 . The composition of  claim 28 , wherein the ACTH analog peptide comprises the peptide of SEQ ID NO: 2 with at least one of the following amino acid substitutions: 
 a. the substitution of the Pro residue at position 19 of SEQ ID NO:2 with the amino acid Trp; or    b. one or more amino acid substitutions of residues selected from amino acid residues 16 to 18 of SEQ ID NO:2, such that: 
 i. the amino acid residues 16, 17 and 18 of the ACTH analog peptide do not include any two adjacent amino acid residues selected from the group consisting of: Lys and Arg; and  
 ii. the one or more amino acid residues substituted at position 16, 17 or 18 of SEQ ID NO:2 are selected from the group consisting of: Lys, Arg, Ala, Gly, Val, Leu, Ile, an amino acid analog comprising an alkyl side chain, Gln, Asn, Glu, and Asp.  
   
     
     
         30 . The composition of  claim 28 , wherein the ACTH analog peptide includes the amino acid sequence -Lys 15 -Arg 16 -Ala 17 -Ala 18 -Trp 19 - at amino acid residues 15-19.  
     
     
         31 . The composition of  claim 28 , wherein the ACTH analog peptide comprises at least one amino selected from the group consisting of SEQ ID NOS: 3-19 and SEQ ID NO: 21.  
     
     
         32 . The composition of  claim 28 , wherein the ACTH analog peptide further comprises the peptide of SEQ ID NO:21 at amino acid positions 25-39.  
     
     
         33 . The composition of  claim 32 , wherein the ACTH analog peptide consists essentially of the peptide of SEQ ID NO:1 with one or more amino acid substitutions.  
     
     
         34 . The composition of  claim 28 , wherein the ACTH analog peptide reduces the ACTH-induced production of corticosterone by adrenal membrane in an in vitro Serum Corticosteroid Induction Assay by at least 10% compared to the unmodified peptide of SEQ ID NO:2, and wherein the at least one amino acid substitution includes substitution of an amino acid residue at one or more amino acid positions selected from the group consisting of amino acid positions: 14, 15, 16, 17, 18 and 19 of SEQ ID NO:2.  
     
     
         35 . The composition of  claim 28 , wherein the ACTH analog peptide further comprises SEQ ID NO:21 at positions 25 to 39.  
     
     
         36 . A method of treating an ACTH-related condition comprising the step of administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an ACTH analog peptide, wherein the therapeutically effective amount is effective to lower the corticosteroid measured in the blood of the subject after the administration of the pharmaceutical composition.  
     
     
         37 . The method of  claim 36 , wherein the administration of the ACTH analog peptide before or simultaneously with administration of an corticosteroid-producing amount of an ACTH peptide comprising SEQ ID NO:2 reduces the serum corticosterone level measured after the administration of the ACTH peptide compared to the serum corticosterone level measured without the administration of the ACTH analog peptide.  
     
     
         38 . The method of  claim 37 , wherein the ACTH peptide is hACTH.  
     
     
         39 . The method of  claim 36 , wherein the administration of the ACTH analog peptide in an in vivo Serum Corticosteroid Inhibition Assay reduces ACTH-induced corticosteroid secretion by at least 90%.  
     
     
         40 . The method of  claim 36 , wherein the ACTH-related condition is selected from the group consisting of: Cushing's Syndrome, impaired immune response and premature labor.  
     
     
         41 . The method of  claim 36 , wherein the ACTH analog peptide comprises an amino acid sequence selected from the group consisting of: 
 a. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Arg-Ala-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    b. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Ala 15 -Lys-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    c. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Ala-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    d. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Ala-Arg-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    e. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Gln 15 -Lys-Gln-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    f. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Ala 15 -Ala-Ala-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    g. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Arg-Ala-Ala-Trp-Val 20 -Lys-Val-Tyr-Pro-;    h. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Ala 15 -Lys-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    i. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Ala-Ala-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    j. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Ala-Arg-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-;    k. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Gln 15 -Lys-Gln-Arg-Pro-Val 20 -Lys-Val-Tyr-Pro-;    l. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gln-Lys 15 -Arg-Ala-Ala-Pro-Val 20 -Lys-Val-Tyr-Pro-; and    m. N-Ser 1 -Tyr-Ser-Met-Glu 5 -His-Phe-Arg-Trp-Gly 10 -Lys-Pro-Val-Gly-Lys 15 -Lys-Arg-Arg-Pro-Ala 20 -Ala-Ala-Ala-Ala-.