Claims for Patent: 7,078,381

Summary for Patent: 7,078,381

Title:	Method of regulating glucose metabolism, and reagents related thereto
Abstract:	The present invention provides methods and compositions for modifying glucose metabolism and treating Type II diabetes in an animal, along with modifying metabolism of a peptide hormone in an animal. Compositions disclosed herein comprise one or more peptides and/or peptide analogs which include a functional group that reacts with an active site residue of a protease.
Inventor(s):	William W. Bachovchin, Andrew G. Plaut, Daniel Drucker
Assignee:	1149336 Ontario Inc, Tufts Medical Center Inc, Arisaph Pharmaceuticals Inc
Application Number:	US10/794,316
Patent Claims:	1. A method for modifying glucose metabolism of an animal in need of modification of glucose metabolism, comprising conjointly administering to the animal a composition comprising an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents. 2. A method for treating Type II diabetes in an animal in need of treatment therefor, comprising conjointly administering to the animal a composition comprising an inhibitor of dipeptidylpeptidase IV or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents. 3. The method of claim 1 or 2, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 4. The method of claim 1 or 2, wherein the inhibitor has an EC50 for modification of glucose metabolism which is at least one order of magnitude less than its EC50 for immunosuppression. 5. The method of claim 1 or 2, wherein the inhibitor has an EC50 for inhibition of glucose tolerance in the nanomolar or less range. 6. The method of claim 1 or 2, wherein the inhibitor has an EC50 for immunosuppression in the μM or greater range. 7. The method of claim 1 or 2, wherein the inhibitor has a Ki for DPIV inhibition of 10 nM or less. 8. The method of claim 1 or 2, wherein the inhibitor has a Ki for DPIV inhibition of 1.0 nM or less. 9. The method of claim 1 or 2, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala. 10. The method of claim 1 or 2, wherein the inhibitor has a molecular weight less than 7500 amu. 11. The method of claim 1 or 2, wherein the inhibitor is administered orally. 12. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula: wherein A represents a 4–8 membered heterocycle including the N and a Cα carbon; Z represents C or N; W represents CN, —CH═NR5, a functional group which reacts with an active site residue of the targeted protease, or R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, or R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; if Z is N, R3 represents hydrogen, if Z is C, R3 represents hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O —(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, or —(CH2)m—S—(CH2)m—R7, R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; Y1 and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 13. The method of claim 12, wherein W represents CN, —CH═NR5, R5 represents H, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)-R7, —(CH2)-OH, —(CH2)- O-alkyl, —(CH2)-O-alkenyl, —(CH2)-O-alkynyl, —(CH2)-O—(CH2)-R7, —(CH2)-SH, —(CH2)-S-alkyl, —(CH2)-S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and Y1 and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 14. The method of claim 13, wherein the ring A is represented by the formula wherein n is an integer of 1 or 2. 15. The method of claim 13, wherein W represents 16. The method of claim 13, wherein R1 represents wherein R36 is a small hydrophobic group and R38 is hydrogen, or, R36 and R38 together form a 4–7 membered heterocycle including the N and the Cα carbon, as defined for A above; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. 17. The method of claim 13, wherein R2 is absent, or represents a small hydrophobic group. 18. The method of claim 13, wherein R3 is a hydrogen, or a small hydrophobic group. 19. The method of claim 12, wherein R5 is a hydrogen, or a halogenated lower alkyl. 20. The method of claim 13, wherein X1 is a fluorine, and X2 and X3, if halogens, are fluorine. 21. The method of claim 12, wherein the inhibitor is represented by the general formula: wherein R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or R6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R11 and R12 each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R11 and R12 taken together with the O—B—O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 22. The method of claim 12, wherein the inhibitor is represented by the general formula: wherein R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or R6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(C)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m-R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)—(CH2)m-R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 23. The method of claim 1 or 2, wherein the inhibitor is represented by the general formula: wherein R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or R6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; X1, X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 24. The method of claim 13, wherein the inhibitor is represented by the general formula: wherein A represents a 4–8 membered heterocycle including an N and a Cα carbon; W represents CN, —CH═NR5, R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R32 is a small hydrophobic group; R30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; Y1 and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 25. A method for modifying metabolism of a peptide hormone in an animal in need of modification of peptide hormone metabolism, comprising conjointly administering to the animal a composition including one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the metabolism of a peptide hormone in the animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the peptide hormone is selected from growth hormone-releasing factor (GHRF), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory peptide (GIP), helodermin, Peptide YY, and neuropeptide Y. 26. A method for modifying glucose metabolism of an animal, comprising conjointly administering to the animal in need of modification of glucose metabolism, a composition comprising a boronyl peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify the glucose metabolism of the animal but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents. 27. The method of claim 26, wherein the boronyl peptidomimetic is represented in the general formula: wherein each A independently represents a 4–8 membered heterocycle including the N and a Cα carbon; R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or (CH2)n—S—(CH2)m—R7; R3 represents hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R6 represents hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O—-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, or —(CH2)m—S—(CH2)m—R7; R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, or R32 represents a small hydrophobic group; R62 represents lower alkyl or halogen; Y1 and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 28. The method of claim 27, wherein administering the boronyl peptidomimetic reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 29. The method of claim 27, wherein the boronyl peptidomimetic has an EC50 for modification of glucose metabolism which is at least one order of magnitude less than its EC50 for immunosuppression. 30. The method of claim 27, wherein the boronyl peptidomimetic has an EC50 for inhibition of glucose tolerance in the nanomolar or less range. 31. The method of claim 27 wherein the boronyl peptidomimetic has an EC50 for inhibition of glucose tolerance of 10 nM or less. 32. The method of claim 27, wherein the boronyl peptidomimetic has an EC50 for immunosuppression in the μM or greater range. 33. The method of claim 27, wherein the boronyl peptidomimetic is administered orally. 34. A method for modifying glucose metabolism in a glucose intolerant animal, comprising conjointly administering to the animal a composition including one or more protease inhibitors which inhibit DPIV-mediated proteolysis with a Ki in the nanomolar or less range or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents. 35. A method for modifying metabolism of a peptide hormone in a glucose intolerant animal, comprising conjointly administering to the animal a composition including one or more inhibitors of dipeptidylpeptidase IV (DPIV) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents, wherein the inhibitor inhibits DPIV with a Ki in the nanomolar or less range, in an amount sufficient to increase the plasma half-life of the peptide hormone but not sufficient to suppress the immune system of the animal, which peptide hormone is selected from growth hormone-releasing factor (GHRF), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP), gastric inhibitory peptide (GIP), helodermin, Peptide YY and neuropeptide Y. 36. A method for modifying glucose metabolism of a glucose intolerant animal, comprising conjointly administering to the animal a composition including a boronyl peptidomimetic inhibitor of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala or a pharmaceutically acceptable salt thereof, in an amount sufficient to modify glucose metabolism but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents. 37. The method of claim 34, 35 or 36, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 38. The method of claim 34, 35 or 36, wherein the inhibitor has an EC50 for modification of glucose metabolism which is at least one order of magnitude less than its EC50 for immunosuppression. 39. The method of claim 34, 35 or 36, wherein the inhibitor has an EC50 for inhibition of glucose tolerance in the nanomolar or less range. 40. The method of claim 34, 35 or 36, wherein the inhibitor has an EC50 for immunosuppression in the μM or greater range. 41. The method of any of claim 34, 35 or 36, wherein the inhibitor has a Ki for DPIV inhibition of 10 nM or less. 42. The method of claim 34, 35 or 36, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, Ala-Pro, and (D)-Ala-(L)-Ala. 43. The method of claim 34, 35 or 36, wherein the inhibitor has a molecular weight less than 7500 amu. 44. The method of claim 34, 35 or 36, wherein the inhibitor is administered orally. 45. The method of claim 34, 35 or 36, wherein the inhibitor is represented by the general Formula VII: wherein, A represents a 4–8 membered heterocycle including a N and a Cα carbon; Z represents C or N; W represents CN, —CH═NR5, R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; if Z is N, R3 represents a hydrogen; if Z is C, R3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —(C═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 46. The method of claim 45, wherein W represents CN, —CH═NR5, R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; Y1 and Y2 can independently or together be hydroxyl, or taken together Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure which is hydrolyzed to hydroxy groups under physiological conditions; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; and X2 and X3 each represent a hydrogen or a halogen. 47. The method of claim 45, wherein the ring A is represented by the formula wherein, n is an integer of 1 or 2. 48. The method of claim 45, wherein W represents 49. The method of claim 45, wherein R1 represents R36 represents a small hydrophobic group and R38 is hydrogen, or, R36 and R38 together form a 4–7 membered heterocycle including the N and the Cα carbon, as defined for A above; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. 50. The method of claim 45, wherein R2 is absent, or represents a small hydrophobic group. 51. The method of claim 45, wherein R3 is a hydrogen, or a small hydrophobic group. 52. The method of claim 45, wherein R5 is a hydrogen, or a halogenated lower alkyl. 53. The method of claim 45, wherein X1 is a fluorine, and X2 and X3, if halogens, are fluorine. 54. The method of claim 45, wherein the inhibitor is represented by the general formula (VIII): wherein, R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)—O-alkenyl, —(CH 2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R11 and R12 each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R11 and R12 taken together with the O—B—O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 55. The method of claim 45, wherein the inhibitor is represented by the general Formula IX: wherein R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 56. The method of claim 45, wherein the inhibitor is represented by the general formula: wherein, R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; X1, X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 57. The method of claim 45, wherein the inhibitor is represented by the general Formula Xa or Xb: wherein, A represents a 4–8 membered heterocycle including a N and a Cα carbon; W represents —CN, —CH═NR5, R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, (CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R32 is a small hydrophobic group; R30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; Y1 and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 58. A method for treating Type II diabetes in an animal in need thereof, comprising conjointly administering to the animal a composition including one or more inhibitors of a dipeptidylpeptidase or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat Type II diabetes but not sufficient to suppress the immune system of the animal, and one or more other therapeutic agents, wherein the inhibitor is represented by the general Formula I: wherein, A represents a 4–8 membered heterocycle including a N and a Cα carbon; Z represents C or N; W represents CN, —CH═NR5, R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group, or R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; if Z is N, then R3 represents a hydrogen; if Z is C, then R3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)2—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m——R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; Y1 and Y2 can independently or together be OH or an alkoxyl, or taken together Y1 and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure which is hydrolyzed to hydroxy groups under physiological conditions; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 59. The method of claim 58, wherein the ring A is represented by the formula wherein, n is an integer of 1 or 2. 60. The method of claim 58, wherein W represents 61. The method of claim 58, wherein R1 represents R36 represents a small hydrophobic group and R38 is hydrogen, or, R36 and R38 together form a 4–7 membered heterocycle including the N and a Cα carbon; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. 62. The method of claim 58, wherein R2 is absent, or represents a small hydrophobic group. 63. The method of claim 58, wherein R3 is a hydrogen, or a small hydrophobic group. 64. The method of claim 58, wherein R5 is a hydrogen, or a halogenated lower alkyl. 65. The method of claim 58, wherein X1 is a fluorine, and X2 and X3, if halogens, are fluorine. 66. The method of claim 58, wherein the inhibitor is represented by the general Formula (II): wherein, R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R11 and R12 each independently represent hydrogen, an alkyl, or a pharmaceutically acceptable salt, or R11 and R12 taken together with the O—B—O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 67. The method of claim 58, wherein the inhibitor is represented by the general Formula III: wherein, R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 68. The method of claim 58, wherein the inhibitor is represented by the general formula: wherein, R1 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino protecting group, or R6 represents a hydrogen, a halogen, an alkyl, an alkenyl, an alkynyl, an aryl, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-alkyl, —(CH2)m—O-alkenyl, —(CH2)m—O-alkynyl, —(CH2)m—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-alkyl, —(CH2)m—S-alkenyl, —(CH2)m—S-alkynyl, —(CH2)m—S—(CH2)m—R7, R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R7, —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, C(═O)—(CH2)m—R7, or R8 and R9 taken together with the N atom to which they are attached complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; X1, X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 69. The method of claim 58, wherein the inhibitor is represented by the general Formula IVa or IVb: wherein, A represent a 4–8 membered heterocycle including an N and a Cα carbon; W represents CN, —CH═NR5, R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R3 represents a hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —(CH2)m—R7, —(CH2)m—OH, —(CH2)m—O-lower alkyl, —(CH2)m—O-lower alkenyl, —(CH2)n—O—(CH2)m—R7, —(CH2)m—SH, —(CH2)m—S-lower alkyl, —(CH2)m—S-lower alkenyl, or —(CH2)n—S—(CH2)m—R7; R5 represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —C(X1)(X2)X3, —(CH2)m—R7, —(CH2)n—OH, —(CH2)n—O-alkyl, —(CH2)n—O-alkenyl, —(CH2)n—O-alkynyl, —(CH2)n—O—(CH2)m—R7, —(CH2)n—SH, —(CH2)n—S-alkyl, —(CH2)n—S-alkenyl, —(CH2)n—S-alkynyl, —(CH2)n—S—(CH2)m—R7, —C(O)C(O)NH2, or —C(O)C(O)OR′7; R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R′7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; R30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group; R32 is a small hydrophobic group; R50 represents O or S; R51 represents N3, SH, NH2, NO2 or OR′7; R52 represents hydrogen, a lower alkyl, an amine, OR′7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 70. The method of claim 69, wherein the ring A is represented by the formula wherein, n is 1 or 2. 71. The method of claim 69, wherein R2 is absent, or represents a small hydrophobic group. 72. The method of claim 69, wherein R3 is a hydrogen, or a small hydrophobic group. 73. The method of claim 58, wherein the inhibitor is peptidomimetic of a peptide selected from Pro-Pro, and Ala-Pro. 74. The method of claim 58, wherein the inhibitor has an EC50 for immunosuppression in the μM or greater range. 75. The method of claim 58, wherein the inhibitor is administered orally. 76. The method of claim 58, wherein administering the inhibitor reduces one or more of insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, or hyperlipoproteinemia. 77. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, wherein said conjointly administering is achieved by simultaneous dosing of the individual components. 78. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, wherein said conjointly administering is achieved by sequential dosing of the individual components. 79. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, wherein said conjointly administering is achieved by separate dosing of the individual components. 80. A method of any one of claims 1, 2, 25, 27, 34, 35, 36, or 58, wherein said conjointly administering is achieved by dosing the individual components in the same composition. 81. A method of any one of claims 1, 2, 25, 26, 34, 35, 36, or 58, further comprising administering the inhibitor or composition in conjunction with a pharmaceutically acceptable carrier.