Calcitonin analogue, and derivative thereof and use thereof

Abstract

A calcitonin analogue, and a derivative or a pharmaceutically acceptable salt thereof. A pharmaceutical composition, containing the analogue or the derivative or pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable excipient. The use of the analogue or the derivative or pharmaceutically acceptable salt thereof and the composition in the field of disease prevention / treatment.

Description

The present application relates to the technical field of polypeptides, specifically, a calcitonin analogue and a derivative and use thereof. BACKGROUND Amylin, a polypeptide hormone consisting of 37 amino acids, is co-secreted with insulin in islet P cells and is lacking in patients with diabetes. It functions in several different organ systems primarily by virtue of amylin receptors 1-3 (AMYRs 1-3). Amylin can inhibit secretion of glucagon, delay gastric emptying, give a signal of satiety, and suppress appetite. Clinical studies have shown that amylin receptor agonists may be used for treating overweight, obesity, type 1 diabetes and / or type 2 diabetes. An amylin analogue known as Pramlintide (Trade name Symlin) may reduce the level of blood glucose and be used to treat patients having diabetes and taking insulin. However, Pramlintide has a half-life of less than an hour and is for mealtime administration, and thus a patient needs to take this medicine for treatment multiple times a day. Due to its instability and a pronounced disposition towards fibrillation at a neutral pH, which results in its precipitation and thus ineffectiveness, Pramlintide is provided in an acidic solution. Calcitonin is a hormone produced in the thyroid gland that regulates levels of calcium and phosphates in the blood, and calcitonin receptors are found in many tissues throughout the body and involved in the regulation of bone remodeling. Salmon calcitonin currently marketed under the name of Miacalcic is useful in the treatment of diseases such as hypercalcemia and osteoporosis. Calcitonin is also unstable at a neutral pH and is thus provided in an acidic solution. Salmon calcitonin has a half-life of less than two hours and needs to be administered to a patient once or more per day. Calcitonin drugs currently available in the market are salmon calcitonin and elcatonin (eel calcitonin), which require daily administration by injection because of their low molecular weight. In addition, only exhibiting a desirable stability under acidic conditions but not under neutral ones poses a great barrier to the pharmaceutical use and formulation development of those molecule. The short half-life of natural amylin and calcitonin receptor agonists has made prolongation of the half-life a target in developing such drugs. In addition, as a result of the poor stability and strong inclination to fibrillation of amylin and calcitonin receptor agonists at a neutral pH, improving stability at physiological pH has become another target in drug development. SUMMARY OF THE INVENTION Accordingly, the present application makes improvements on agonistic polypeptides against amylin receptors so as to obtain analogues or their derivatives or pharmaceutically acceptable salts thereof, with an enhanced efficacy in vivo and an increased stability. Specifically, the present application is directed to the following technical solution: a derivative of calcitonin or a pharmaceutically acceptable salt thereof, comprising a polypeptide with an amino acid sequence of Xo X1SX3LS TX7VLG RLSXmE LHRLX20 X2iX22PRT X26X27GX29X30 S X32-NH2, wherein: Xo is D or E, or is absent; Xiis A, L, V, I, S, E,RorK; X3 is Q, E or D; X7 is A, L, V, I, S, R, E or D; Xh is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; X29 is S or A; X30 is G or E; and X32 is P or trans-Hyp. In a preferred embodiment, the derivative of calcitonin or a pharmaceutically acceptable salt thereof comprises a polypeptide with the following amino acid sequence: V V CV T 0 TV X TT C' D T 0 V T7 T T ID T V V V DDT V V V V 0 V Xo X10X3L0 IX7VLU KLdXut LHKLX20 X21X22I K1 X26X27VJX29X30 o X32-nh2, wherein: Xo is D or E or is absent; a combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E, R-D, K-E, K-D or E-E; X3isQ,EorD; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22is Y,LorF; X26 is D or Q; X27 is V or S; a combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X2I is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D; Xh is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D, XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q; Xu is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q; Xu is Q, D, E, Aib, S or T; X20 is Q or E; X2i is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or E-E, X3 is D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or E-E, X3 is E; Xu is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; Xw is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D, Xi4 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D, Xi4 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q, X27 is V or S, the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D, Xi4 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D, Xi4 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D, Xu is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; Xu is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; Xu is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; XM is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q, E or D; Xw is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D; Xu is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; X14 is Q, D or E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or R-D, or K-E, or K-D or E-E, X3 is Q, E or D; X14 is Q; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or R-D, or K-E, or K-D or E-E, X3 is Q, E or D; X14 is D; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or R-D, or K-E, or K-D or E-E, X3 is Q, E or D; X14 is E; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or R-D, or K-E, or K-D or E-E, X3 is Q, E or D; X14 is Aib; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or R-D, or K-E, or K-D or E-E, X3 is Q, E or D; X14 is S; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or R-D, or K-E, or K-D or E-E, X3 is Q, E or D; X14 is T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, or L-L, or V-V, or I-I, or S-S, or A-S, or S-A, or E-R, or R-E, or R-D, or K-E, or K-D or E-E, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is E; X21 is D or E; X22 is Y, L or F; and the combination of X29-X30 is selected from S-G, A-G, A-E or S-E. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; XH is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q, E or D; XH is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; Xh is Q, D, E, Aib, S or T; X20 is Q; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D; XH is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X2i is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X2? is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; XH is Q, D, E, Aib, S or T; X20 is Q or E; X21 is E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D; Xh is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D; XH is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D; Xh is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; XH is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X2i is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D; Xj4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D; X]4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X2i is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; XH is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or transHyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, 1-1, S-S. A-S, S-A, E-R, R-E or E-E; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; a combination of X26-X27 is D-V; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, 1-1, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; the combination of X26-X27 is Q-S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; X m is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; the combination of X26-X27 is Q-V; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; the combination of X26-X27 is D-S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-A, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is L-L, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or trans- Hyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is V-V, X3 is Q, E or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is I-I, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-S, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is A-S, X3 is Q, E or D; XH is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is S-A, X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-R, X3 is Q, E or D; Xu is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-E, X3 is Q, E or D; Xm is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is R-D, X3 is Q, E or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is D-E, X3 is Q, E or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is K-D, X3 is Q, E or D, XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent, the combination of Xi and X7 is E-E, X3 is Q, E or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-G; and X32 is P or transHyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is A-G; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is A-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; Xi4 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P. In a preferred embodiment, Xo is absent; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; XH is Q, D, E, Aib, S or T; X20 is Q or E; X2i is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is transHyp. In a preferred embodiment, Xo is D; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X2i is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or transHyp. In a preferred embodiment, Xo is E; the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E or E-E; X3 is Q or D; X14 is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y, L or F; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or transHyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, R-E, R-D, K-E or K-D; X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X2i is D or E; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, R-E, R-D, K-E or K-D; X3 is Q, E or D; X]4 is Q, D, E, Aib, S or T; a combination of X20-X2i is E-E; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X- is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, R-E, R-D, K-E or K-D, X3 is Q, E or D; a combination of Xi4-X22 is D-L; X2o is Q or E; X2i is D or E; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, R-E, R-D, K-E or K-D, X3 is Q, E or D; Xu is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y or L; X26-X27 is Q-S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, R-E, R-D, K-E or K-D, X3-X14-X20 is E-E-E; X21 is D or E; X22 is Y or L; X26 is D or Q; X77 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, or R-E; X3 is Q, E or D; XM is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y or L; X26 is D or Q; X77 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, or R-E; X3 is Q, E or D; Xu is Q, D, E, Aib, S or T; X20-X21 is E-E; X22 is Y or L; X26 is D or Q; X77 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, or R-E; X3 is Q, E or D; XM-X22 is D-L; X20 is Q or E; X21 is D or E; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, or R-E, X3 is Q, E or D; Xu is Q, D, E, Aib, S or T; X20 is Q or E; X21 is D or E; X22 is Y or L; X26-X77 is Q-S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, Xo is D or E or is absent, the combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, or R-E, X3-X14-X20 is E-E-E; X21 is D or E; X22 is Y or L; X26 is D or Q; X27 is V or S; the combination of X29-X30 is selected from S-G, A-G, A-E or S-E; and X32 is P or trans-Hyp. In a preferred embodiment, the derivative or a pharmaceutically acceptable salt thereof comprises a polypeptide with an amino acid sequence of ASQLS TAVLG RLSX14E LHRLX20 DX22PRT DVGX29G SP-NH2, wherein, X14 is Q, D or E; X20 is Q or E, preferably Q; X22 is Y or L; and X29 is S or A. In a preferred embodiment, the derivative or a pharmaceutically acceptable salt thereof comprises a polypeptide with an amino acid sequence of ASQLS TAVLG RLSX14E LHRLQ DX22PRT DVGSG SP-NH2, wherein, X14 is Q, D or E, preferably Q or D; and X22is YorL. In a preferred embodiment, the derivative of calcitonin or a pharmaceutically acceptable salt thereof comprises an amino acid sequence selected from any one of SEQ ID NO. 1-SEQ ID NO. 38 in Table 2. In a preferred embodiment, the derivative of calcitonin or a pharmaceutically acceptable salt thereof comprises an amino acid sequence selected from any one of: ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 (SEQ ID NO. 7), ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH2 (SEQ ID NO. 17), ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 (SEQ ID NO. 8), ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH2 (SEQ ID NO. 18), ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH2 (SEQ ID NO. 19) or ASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH2 (SEQ ID NO. 12). In a preferred embodiment, the derivative of calcitonin or a pharmaceutically acceptable salt thereof comprises a side chain, preferably a fatty acid-containing side chain, for modifying the amino acids. In a preferred embodiment, the derivative of calcitonin or a pharmaceutically acceptable salt thereof comprises a fatty acid-containing side chain linked to the N terminus of the amino acid sequence. In a preferred embodiment, the fatty acid-containing side chain is in the form of Z1+Z2+Z3, wherein Z1 is a C16-C22 fatty diacid; Z2 is selected from any one of yGlu, aGlu, PAsp, aAsp, Inp, and Trx, or is absent; and Z3 is n AEEA(s), wherein n>0. Zl, Z2, and Z3 are linked via amide linkages. In a preferred embodiment, n is selected from 0, 1,2, 3, 4, 5 or 6. In a preferred embodiment, n is 6. In a preferred embodiment, n is 4. In a preferred embodiment, n is 2. In a preferred embodiment, n is 0. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + yGlu. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + aGlu. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + PAsp. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + aAsp. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + Inp. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + Trx. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid). In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + yGlu+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + yGlu+4 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + yGlu+6 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + aGlu+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + pAsp+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + aAsp+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + Inp+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C16-C22 fatty diacid) + Trx+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + yGlu. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + aGlu. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + pAsp. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + aAsp. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + Inp. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + Trx. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid). In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + yGlu+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + yGlu+4 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + yGlu+6 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + aGlu+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + pAsp+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid)+ aAsp+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + Inp+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C20 fatty diacid) + Trx+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C22 fatty diacid) + yGlu+2 AEEAs. In a preferred embodiment, the fatty acid-containing side chain is in the form of (C22 fatty diacid) + yGlu+4 AEEAs. The present application also provides a polypeptide analogue, which is a polypeptide comprising an amino acid sequence of any one of the derivatives described above. The present application also provides a pharmaceutical composition comprising one or more of the analogue, or the derivative or a pharmaceutically acceptable salt thereof described hereinabove. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, e.g., a nontoxic filler, stabilizer, diluent, carrier, solvent, or the like. The present application also provides use of the analogue, or the derivative or a pharmaceutically acceptable salt thereof described above in the manufacture of a medicament for preventing and / or treating overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain. The present application also provides use of the analogue, or the derivative or a pharmaceutically acceptable salt thereof described above in reducing food intake and / or body weight, for example, use thereof in the manufacture of a healthcare product, food, or medicament for reducing food intake and / or body weight. The present application also provides a method of preventing and / or treating overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain, comprising administering to a subject a prophylactically or therapeutically effective amount of the analogue, the derivative or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described hereinabove. The present application also provides a method of reducing food intake, comprising administering to a subject an effective amount of the analogue, the derivative, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described hereinabove. BRIEF DESCRIPTION OF THE DRAWINGS The drawings are intended for a better understanding rather than any undue limitation of the present application, in which: FIG. 1 is the spectrum of reversed phase chromatography of the molecule D3 (Mimylin) on Day 26 of a heat accelerated assay; FIG. 2 is the spectrum of reversed phase chromatography of the calcitonin analogue M5 on Day 26 of a heat accelerated assay; FIG. 3 is the spectrum of reversed phase chromatography of the molecule M8 alone on Day 26 of a heat accelerated assay under a neutral condition; FIG. 4 is the spectrum of reversed phase chromatography of M8 and M51 in a neutral buffer solution without excipients after one month of a heat accelerated assay; FIG. 5 is the spectrum of reversed phase chromatography of M8 and M51 in a neutral buffer solution with excipients after one month of a heat accelerated assay; FIG. 6 is a trend chart showing the effect of the first group of calcitonin analogues or derivatives on weight change of rats in the experiment; FIG. 7 is a trend chart showing the effect of the first group of calcitonin analogues or derivatives on accumulated food intake of rats in the experiment; FIG. 8 is a trend chart showing the effect of the second group of calcitonin analogues or derivatives on weight change of rats in the experiment; and FIG. 9 is a trend chart showing the effect of the second group of calcitonin analogues or derivatives on accumulated food intake of rats in the experiment. DETAILED DESCRIPTION An “analogue” as described herein refers to a compound formed from a particular polypeptide molecule in which at least one amino acid residue has been substituted with another one, and / or at least one amino acid residue has been deleted, and / or at least one amino acid residue has been added to the N or C terminus, and / or at least one amino acid residue has been inserted between any two amino acids. Terms “polypeptide” and “analogue”, and the corresponding form thereof as used in a composition have the same meaning and are interchangeably used in the present application unless otherwise specified in the context. In certain cases, terms “calcitonin” and “calcitonin analogue” have the same meaning and are interchangeably used, for example in “a derivative of a calcitonin analogue” and “a derivative of calcitonin”. A “derivative” as described herein refers to a product resulting from a modification of a functional group (e.g., an amino acid residue) in a biomacromolecule (e.g., a polypeptide or protein) with certain groups or structures (e.g., structures of certain small molecules). The modification includes but is not limited to acylation, amidation, esterification, and thioesterification. Abbreviations Corresponding names or structures of some abbreviations used in the examples of the present application are as follows: AA: Amino Acid; Boc: t-Butyloxy carbonyl; DCM: dichloromethane; DMF: N,N- Dimethyl formamide; DIEA: N,N-Diisopropylethylamine; EDT: 1,2-Ethanedithiol; Fmoc: 9-fluorenylmethyloxycarbonyl; OtBu: t-butyl ester; Pbf: 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl chloride; Pip: Piperidine; TBTU: O-(Benzotriazol-l-yl)-N,N,N',N',-tetramethyluronium Tetrafluoroborate; tBu: tertiary butyl; TFA: Trifluoroacetic acid; TIS: Triisopropylsilane; Trt: Triphenylmethyl; aGlu: a-glutamic acid; yGlu: y-glutamic acid; aAsp: a-aspartic acid; and pAsp: P-aspartic acid. Illustrative examples of the present application are described as below, in which various details of the examples in the present application are included for ease of understanding and should be construed as illustrative only. Therefore, it is to be realized by those of ordinary skill in the art that many alterations and modifications may be made to the examples described here without departing from the scope and spirit of the present application. For clarity and conciseness, the following description also omits depiction of well known functions and structures. EXAMPLES Example 1 Preparation of Polypeptide Derivatives The polypeptides were synthesized by solid phase organic synthesis, specifically, solid-phase peptide synthesis (SPPS) with Fmoc-protected amino acids, and then cleaved, oxidized, and purified to yield target products. Taking the compound Cagrilintide (designated as “DI”) as an example, the synthesis process was as below. 1.1 Solid-phase synthesis Using Fmoc-Linker MBHA Resin S=0.32 mmol / g and employing Fmoc / tBu processing, amino acids were linked by sequential condensation from the C terminus to the N terminus (from right to left) as per the sequence of the aforesaid peptide in accordance with the method provided in Table 1. Table 1. Listing of synthesis procedures No. Solvent Number of times duration (min / time) 1 20% Pip / DMF 1 10 2 20% Pip / DMF 1 5 3 DMF 5 1 4 Sampling for colorimetric testing 5 AA / DIEA / TBTU 1 60 6 DMF 4 1 7 Sampling for colorimetric testing Notes 1. Repeating 1-7 till the end of the linear peptide synthesis The following amino acids were coupled in order: A-01 Fmoc-Pro-OH, A-02 Fmoc-Thr(tBu)-OH, A-03 Fmoc-Asn(Trt)-OH, A-04 Fmoc-Ser(tBu)-OH, A-05 Fmoc-Gly-OH, A-06 Fmoc-Val-OH, A-07 Fmoc-Asn(Trt)-OH, A-08 Fmoc-Thr(tBu)-OH, A-09 Fmoc-Pro-OH, A-10 Fmoc-Pro-OH, A-l 1 Fmoc-Leu-OH, A-12 Fmoc-Ile-OH, A-13 Fmoc-Pro-OH, A-14 Fmoc-Gly-OH, A-15 Fmoc-Phe-OH, A-16 Fmoc-Asn(Trt)-OH, A-17 Fmoc-Asn(Trt)-OH, A-l8 Fmoc-Ser(tBu)-OH, A-19 Fmoc-Ser(tBu)-OH, A-20Fmoc-His(Trt)-OH, A-21 Fmoc-Arg(Pbf)-OH, A-22 Fmoc-Leu-OH, A-23 Fmoc-Phe-OH, A-24 Fmoc-Glu(OtBu)-OH, A-25 Fmoc-Ala-OH, A-26 Fmoc-Leu-OH, A-27 Fmoc-Arg(Pbf)-OH, A-28 Fmoc-Gln(Trt)-OH, A-29 Fmoc-Thr(tBu)-OH, AGO Fmoc-Ala-OH, A-31 Fmoc-Cys(Trt)-OH, A-32 Fmoc-Thr(tBu)-OH, A-33 Fmoc-Ala-OH, A-34 Fmoc-Thr(tBu)-OH, A-35 Fmoc-Asn(Trt)-OH, A-36 Fmoc-Cys(Trt)-OH, A-37 Fmoc-Lys(Boc)-OH, A-38 Fmoc-Glu-otbu, and A-39 C20 diacid. Finally, a polypeptide derivative-on-resin was formed. The polypeptide derivative-on-resin was washed, transferred out, and dried to a constant weight for cleavage. 1.2 Cleavage Formulation of a cleavage reagent: the cleavage reagent was TFA:H2O:EDT:TIS = 95:1:2:2, the amount of which was a volume of 10 mL±2 mL per 1 g of the peptide-on-resin. H2O, TFA, EDT, and TIS composing the required cleavage reagent were sequentially added to a cleavage reaction flask and were controlled at a temperature of 0-10°C. The cleavage reagent was added to the resin under stirring, and after the temperature of the system became stable, the reactants were stirred for another 2.5 hours under a controlled temperature of 25-30°C. The cleavage solution was filtered, and allowed for precipitation using glacial diethyl ether of a 5x volume of the liquid. The precipitates were filtered, washed 3 times with glacial diethyl ether of a 3x volume of 31 the liquid, and then dried under reduced pressure at room temperature to yield a solid crude. 1.3 Oxidation The crude was finely ground, and was slowly added, with stirring, to purified water, while an aqueous solution of acetonitrile was added dropwise. After the crude was added and completely dissolved, a methanol solution of iodine was added and stirred for half an hour. 1.4 Purification and lyophilization The oxidated liquid as described above was filtered with a 0.45 um microporous filtering membrane. The crude was separated and purified using a column prepared by C-18 column packing material with a suitable gradient at ambient temperature, and then the target product was collected, detected and analyzed, and sorted. A purity >90% was required. Substandard target products were collected, and separated and purified again with a suitable gradient, to achieve qualified liquid peaks. The qualified liquid samples as mentioned above were lyophilized under reduced pressure to yield lyophilized powder of the refined polypeptide. Polypeptides and derivatives prepared using a similar method to that described in Example 1 of the present application are shown in Table 2. D2 denotes the sequence of natural salmon calcitonin, DI and D3 represent the sequences of modified calcitonins in the prior art, and the remaining are calcitonin analogues or derivatives provided in the present application, wherein the fatty diacid moiety of the polypeptide derivative is located at the outer side of the fatty acid-containing side chain for modification relative to the amino acid sequence, and thus is positioned at the distal end of the linkage of the side chain to the amino acid sequence. Table 2. Amino acid sequences and modifications ID SEQ ID NO. Amino acid sequence Site of modifica tion Fatty acidcontaining side chain DI SEQ ID NO. 1 KCNTATCATQ RLAEFLRHSS NNFGPILPPT NVGSNTP-NH2 terminus C20 diacid + yGlu D2 SEQ ID NO. 2 qxtT Q npz^ x rr t / t CfYE T T TT^T o 1N 1_ / o 1 V JL / vJ TYPRT NTGSG TP-NH2 None None D3 SEQ ID NO. 3 EASEL STAAL GRLSA ELHEL None None ATLPR TETGP ESP-NH2 M5 SEQ ID NO. 5 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 None None M6 SEQ ID NO. 5 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M7 SEQ ID NO. 6 ASDLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M8 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M9 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu MIO SEQ ID NO. 9 ASQLS TAVLG RLS-Aib-E LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu Mil SEQ ID NO. 10 ASQLS TAVLG RLSSE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M12 SEQ ID NO. 11 ASQLS TAVLG RLSTE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M13 SEQ ID NO. 12 ASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M14 SEQ ID NO. 13 ASQLS TAVLG RLSQE LHRLE EYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M15 SEQ ID NO. 14 ASQLS TAVLG RLSQE LHRLQ DYPRT QVGSG SP-NH2 terminus C20 diacid + yGlu M16 SEQ ID NO. 15 ASQLS TAVLG RLSQE LHRLQ DYPRT DSGSG SP-NH2 terminus C20 diacid + yGlu M17 SEQ ID NO. 16 ASQLS TAVLG RLSQE LHRLQ DYPRT QSGSG SP-NH2 terminus C20 diacid + yGlu M18 SEQ ID NO. 17 ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M19 SEQ ID NO. 18 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH2 terminus C20 diacid + yGlu M20 SEQ ID NO. 19 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH2 terminus C20 diacid + yGlu M21 SEQ ID NO. 20 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSE SP-NH2 terminus C20 diacid + yGlu M22 SEQ ID NO. 21 ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG S-tra«5-Hyp -NH2 terminus C20 diacid + yGlu M23 SEQ ID NO. 22 D ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C18 diacid M24 SEQ ID NO. 23 E ASQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C18 diacid M25 SEQ ID NO. 24 LSQLS TLVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M26 SEQ ID NO. 25 VSQLS TVVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M27 SEQ ID NO. 26 ISQLS TIVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M28 SEQ ID NO. 27 SSQLS TSVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M29 SEQ ID NO. 28 ASQLS TSVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M30 SEQ ID NO. 29 SSQLS TAVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M31 SEQ ID NO. 30 ESQLS TRVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M32 SEQ ID NO. 31 RSQLS TEVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M33 SEQ ID NO. 32 ESQLS TEVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M34 SEQ ID NO. 33 ASELS TAVLG RLSEE LHRLE DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu M3 5 SEQ ID NO. 34 RSQLS TDVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid+yGlu M3 6 SEQ ID NO. 35 KSQLS TEVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid+yGlu M37 SEQ ID NO. 36 KSQLS TDVLG RLSQE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid+yGlu M3 8 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C22 diacid + yGlu M39 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C18 diacid + yGlu M40 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C16 diacid + yGlu M41 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + aGlu M42 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C18 diacid + aGlu M43 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + pAsp M44 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C18 diacid + a Asp M45 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + Trx M46 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C18 diacid + Trx M47 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 di acid + Inp M48 SEQ ID NO. 7 ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2 terminus C18 diacid + Inp M49 SEQ ID NO. 37 ASQLS TAVLG RLSQE LHRLQ DFPRT DVGSG SP-NH2 terminus C20 diacid+yGlu M50 SEQ ID NO. 38 ASQLS TAVLG RLSDE LHRLQ DLPRT DVGSG SP-NH2 terminus C20 diacid+yGlu M51 SEQ ID NO. 4 HVEGTFTSDVSSYLEEQAAREFI KWLVRGRG-OH 30K C18 diacid+yGlu +2 AEEAs M52 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid+aGlu M53 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid+pAsp M54 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid+aAsp M55 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + fix M56 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + Inp M57 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid+yGlu+2 AEEAs M58 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + aGlu+2 AEEAs M59 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + PAsp+2 AEEAs M60 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + aAsp+2 AEEAs M61 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + Trx+2 AEEAs M62 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + Inp+2 AEEAs M63 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu+4 AEEAs M64 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C20 diacid + yGlu+6 AEEAs M65 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C22 diacid+yGlu M66 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C22 diacid + yGlu+2 AEEAs M67 SEQ ID NO. 8 ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2 terminus C22 diacid + yGlu+4 AEEAs Example 2 Testing for Activity of the Derivatives in Cells The objective of this assay is to test the activity or potency of calcitonin analogues or derivatives on human amylin receptors in vitro using a luciferase assay. 2.1 Construction of an amylin receptor / CRE-luc cell line Using the standard protocol, CHO-Kl / Gal5 / AMY3 cells (purchased from GenScript, with the calcitonin receptor and the receptor activity modifying peptide (RAMP) constructed already) were transfected with a plasmid containing a luciferase expression cassette driven by multiple copies of cAMP response elements (CREs). The cells were cultured in an F12 medium containing 200 ug / mL Zeocin, 2 ug / mL puromycin, 100 ug / mL hygromycin, and 400 ug / mL G418 to afford a stably transfected amylin receptor / CRE-luc cell line. 2.2 Luciferase assay of amylin The lyophilized powder obtained according to the method of Example I was dissolved in 20 mM phosphate buffer solution with a pH of 7.0, and diluted in a growth medium (Fl2 culture medium containing 10% FBS) to give a derivative sample with an initial concentration of 10 nM, which was then subjected to a 5-fold serial dilution in the growth medium to afford samples of 7 concentrations including 10 nM, 2 nM, 0.4 nM, etc. To each well of a white 96-well plate was added 50 pL of the tested sample solution at a respective concentration. The stably transfected amylin receptor / CRE-luc CHO cells were resuspended in the growth medium at a certain density, and 50 pL of the cell suspension was added at a density of about 20000 cells per well to the white 96-well plate containing the tested sample solution. After incubation of 24 hours at 37°C and 5% CO2, 100 pL of a Luciferase substrate was added to each well, incubated for 3 minutes, and finally was tested for luminescence on SpectraMax L (Molecular Devices) with the software SoftMax Pro 7.0.3 GxP. A standard curve was plotted using the fluorescent intensities for calculation of EC50. Results were shown in Table 3 as below. Table 3. Results for activity against amylin receptors in cells ID EC50 / nM ID EC50 / nM ID EC50 / nM ID EC50 / nM DI 0.036 M19 0.016 M3 6 0.032 M53 0.017 D4 0.031 M20 0.017 M3 7 0.052 M54 0.017 M5 0.033 M21 0.017 M3 8 0.022 M55 0.017 M6 0.017 M22 0.017 M39 0.016 M56 0.017 M8 0.017 M23 0.010 M40 0.002 M57 0.017 M9 0.017 M24 0.016 M41 0.069 M58 0.017 M10 0.016 M25 0.016 M42 0.016 M59 0.017 Mil 0.017 M26 0.079 M43 0.017 M60 0.016 M12 0.017 M27 0.016 M44 0.016 M61 0.015 M13 0.017 M28 0.017 M46 0.119 M62 0.016 M14 0.017 M29 0.017 M47 0.082 M63 0.037 M15 0.016 M30 0.017 M48 0.063 M64 0.044 M16 0.025 M32 0.030 M49 0.075 M65 0.017 M17 0.042 M34 0.058 M50 0.017 M66 0.017 M18 0.028 M3 5 0.037 M52 0.017 M67 0.017 The data in the table demonstrated that most of the calcitonin analogues or derivatives provided in the present application had strong activity against amylin receptors in cells, and some of the derivatives even had an activity value that was one order of magnitude higher than calcitonin analogues or derivatives in the prior art. Example 3 Heat Accelerated Stability Assay 3.1 Materials and devices A stability test chamber (BINDER GmbH), a 0.01 mg-readability balance (METTLER TOLEDO), a pH meter (METTLER TOLEDO), a biosafety cabinet (ESCO), T2G-II small-sized motor-driven capping machine (Changsha zhongya pharmaceutical equipment co. LTD), a high-speed refrigerated centrifuge (Eppendorf), a sterilizer cabinet (Shinva Medical), Agilent 1260 high-performance liquid chromatographer, and Sepax Bio-C 18 4.6*250 mm 3 pm 200 A reversed phase column were used. Reagents and consumables included ultrapure water (18.2 MQ, self-made), acetonitrile (HPLC grade), trifluoroacetic acid (HPLC grade), sodium dihydrogen phosphate (pharmaceutical grade, Hunan Jiudian Hongyang Pharmaceutical Co., Ltd), hydrochloric acid (pharmaceutical grade, Hunan Er-Kang Pharmaceutical Co., Ltd), sodium hydroxide (Analytical Reagent grade, Hushi®, Sinopharm Chemical Reagent Co., Ltd), vials, rubber stoppers, disposable syringes, and sterile filters. 3.2 Methods of the assay The lyophilized powder (1 mg / mL) of calcitonin analogues or derivatives prepared in accordance with the method of Example 1 were mixed with sodium dihydrogen phosphate (1.42 mg / mL) and dissolved in ultrapure water in the indicated mass-volume ratios. After adjusting pH to about 7.4 with hydrochloric acid / sodium hydroxide, the solution was filtered into a sterilized vial in a clean bench using a 0.22 pm sterile filter. The vial was then capped and placed into the stability test chamber at 40°C. Detections were made on Days 7 (7d) and 26 (26d), and during the assay, changes in the characteristics and properties of the polypeptides were observed and recorded. The sample was then centrifuged for 3 min at 10000 rpm at 4°C, and the supernatant was transferred to a liquid phase sample vial for detecting the concentration and purity of the polypeptides using liquid phase chromatography described as below, wherein the concentration of the polypeptide = peak area / inj ection volume / extinction coefficient / 60flow rate, and the purity of the polypeptide = target peak area / total peak area* 100%. Conditions of the reversed phase chromatography Flow rate: 1.0 ml / min; Autosampler temperature: 15°C; Column temperature: 25°C; Detection wavelengths: 280 nm and 214 nm; Mobile phase A: 100% H20+0.05% TFA; Mobile phase B: 100% ACN; and Gradient of elution listed in Table 4: Table 4. Listing of the gradient of elution in the liquid phase chromatography Time (min) 0 3 8 13 14 20 B% 25 25 70 70 25 25 3.3 Results of the assay Results were shown below in Tables 5, 6, and 7. A difference of more than 5% in content as compared with the initial value was typically assumed (for example, as prescribed by the Chinese Pharmacopeia (2020 Edition)) to be a significant change. Within a reasonable margin of error, a decrease of less than 1% from the initial value to the detected content is denoted as “no change” below. Table 5, Changes in characteristics or properties in the heat accelerated stability assay ID 0d 7d ID 0d 7d ID Od 7d DI Clear Clear M16 Clear Clear M40 Clear Clear D2 Clear Clear M19 Clear Clear M41 Clear Clear D3 Clear Clear M22 Clear Clear M42 Clear Clear M5 Clear Clear M24 Clear Clear M43 Clear Clear M7 Clear Clear M27 Clear Clear M44 Clear Clear M8 Clear Clear M29 Clear Clear M45 Clear Clear M9 Clear Clear M32 Clear Clear M46 Clear Clear M10 Clear Clear M34 Clear Clear M47 Clear Clear Mil Clear Clear M3 8 Clear Clear M48 Clear Clear M13 Clear Clear M39 Clear Clear As shown in Table 5, the calcitonin analogues or derivatives provided in the present application had no noticeable change in characteristics or properties during the heat accelerated stability assay under a neutral condition. The solution was still clear on Day 7 of the accelerated testing, indicating almost no characteristic or property change of the polypeptides. Molecules such as M8, M9 and M13 were further found to exhibit no significant change in characteristics or properties and remain to be in a clear solution even on Day 26 of the accelerated testing, manifesting considerably stable characteristics and properties. Table 6. Concentration changes in the heat accelerated stability assay ID Concentration change (7d-0d) / % ID Concentration change (7d-0d) / % ID Concentration change (7d-0d) / % D2 -40.064 M22 No change M41 -3.134 M5 -1.051 M24 No change M42 -3.344 M7 No change M27 No change M43 No change M8 No change M29 No change M44 -2.285 M9 No change M32 No change M45 -2.670 MIO No change M34 -1.618 M46 No change Mil No change M4 No change M47 -3.488 M13 No change M3 8 No change M48 -1.678 M16 No change M3 9 No change M19 No change M40 -2.280 Table 6 showed that there was no obvious change in concentration of the calcitonin analogues or derivatives provided in the present application during the heat accelerated stability assay under a neutral condition. The concentration changes were all below 4% on Day 7 of the accelerated testing, and were found to be close to 1% (e.g., M5) or even below 1% (denoted as “no change”; e.g., M8 and M13) for some of the calcitonin analogues or derivatives. M8 and M13 had a concentration change of less than 2% even on Day 26 of the accelerated testing as compared to Day 0, exhibiting a high stability in concentration. Table 7. Purity changes in the heat accelerated stability assay (Purity from the reversed phase chromatography-214 nm) ID Change% (7d-0d) Change% (26d-0d) ID Change% (7d-0d) Change% (26d-0d) DI -12.73 / M32 No change / D2 -47.82 / M34 No change / D3 -6.85 -18.00 M4 No change No change M5 No change No change M8 No change -2.21 M7 No change No change M3 8 No change No change M8 No change No change M3 9 No change -3.3 M9 No change No change M40 -1.67 -4.82 M10 No change / M41 -1.66 -5.98 Mil No change / M42 No change -2.93 M13 No change No change M43 No change -1.96 M16 No change / M44 -1.15 -3.76 M19 No change / M45 No change -1.77 M22 No change / M46 No change -5.67 M24 No change / M47 No change No change M27 No change / M48 -1 -3.9 M29 No change Table 7 revealed that there was no significant change in purity of the calcitonin analogues or derivatives provided in the present application during the heat accelerated stability assay under a neutral condition. On Day 7 of the accelerated testing, purity changes of most of the polypeptide solutions were less than 1% as determined by the reversed phase chromatography, or even no purity decrease was observed; and molecules such as M5, M8, M9 and M13 were further found to have a lower change or even nearly no noticeable change in purity on Day 26 of the accelerated testing, showing great stability in purity. In contrast to a purity decrease of 18% in the molecule D3 in the prior art on Day 26 of the heat accelerated assay (see FIG. 1), the purity of the calcitonin analogue M5 of the present application was decreased by only 0.68% at the same timepoint (see FIG. 2). A comparison in purity changes of the calcitonin derivative M8 provided in the present application and DI (Cagrilintide, Novo Nordisk) in the heat accelerated assay was shown in Table 8, and the spectra of reversed phase chromatography of the molecule M8 prior to and after the heat accelerated assay were shown in FIG. 3. The difference between the backbones of M8 and DI was clearly shown by the data from Table 8 and FIG. 3, and the former had an excellent stability under a neutral condition. Table 8. Comparison of results from liquid phase analysis on 26d of the heat _________________accelerated assay_________________ Molecular ID Reversed phase chromatography 7d change 26d change DI -12.73% / M8 No change -0.12% As indicated by the data of the present application, the molecules of calcitonin analogues and derivatives provided herein had significantly higher stability in the heat accelerated assay than those in the prior art. Example 4 Heat Accelerated Stability Assay for Compatibility Testing The calcitonin analogue M8 (1 mg / ml), the GLP-1 receptor agonist M51 (1 mg / ml), and sodium dihydrogen phosphate (1.42 mg / ml) were mixed and dissolved in ultrapure water, and 5.5 mg / ml phenol and 14 mg / ml 1,2-dihydroxypropane were further added for the testing group with excipients. After pH was adjusted to about 7.4 with hydrochloric acid / sodium hydroxide, accelerated stability assays were performed according to the method of Example 3. The results were shown in FIG. 4 (without excipients) and FIG. 5 (with excipients), which demonstrated that M8 was well compatible with M51, showing only a little change in the spectra of reversed phase chromatography after a one-month heat accelerated assay under the same formulation condition with M51. Thus, they had the potential to be developed as a co-formulation. As shown in the results of the present heat accelerated assays, the calcitonin analogues or derivatives provided herein exhibited remarkably good stability, for example the molecule M8, which has excellent thermal stability both as a single drug and when combined with M51 under the same formulation condition. Example 5 Study of Weight Change and Food Consumption in Animals SD (Sprague Dawley) rats weighing 200-250 g were used for this study. The rats were received at least 10-14 days before the study began such that they could accommodate to the experimental environment. After arrival, they were exposed to a reversed light / dark cycle (i.e., lights switched off in daytime and on in nighttime) for two weeks and were individually housed for the first week so as to ensure high data accuracy and test sensitivity. Throughout the acclimation and experiment period, the rats had free access to food and water. 5-8 rats were assigned to each testing group for the derivatives and were subcutaneously administered the derivatives at a dose of 10 nmol / kg or a vehicle, and the dosing timepoint was recorded for each group. After dosing, the rats were put back into cages where they were housed and could have access to food and water. Food consumption and weight change of the rats were recorded online or manually every 24 hours. The first and second groups of experimental results were shown in FIGs. 6 and 7 and FIGs. 8 and 9 respectively, which suggested that the calcitonin analogues and derivatives of the present application produced an appreciable effect on reducing body weight and food intake of the rats. FIGs. 6 and 7 further revealed that the calcitonin analogues of the present application had a superior effect to DI in terms of weight loss and appetite suppression, among which M18, M9 and M13 were particularly effective. FIGs. 8 and 9 further revealed that the calcitonin analogues and derivatives of the present application such as M8, Ml9 and M20 had a prominent effect on both reducing body weight and food intake of the rats. Although embodiments of the present application have been described as above, the present application is not limited to the above specific embodiments, which are only illustrative and directory but not restrictive, and application fields. Without departing from the scope of the claims of the present application, many variants may occur to those of ordinary skill in the art with inspiration from this specification.

Claims

1. A derivative of calcitonin or a pharmaceutically acceptable salt thereof, comprising a polypeptide with an amino acid sequence of Xo X1SX3LS TX7VLG o T C V CT UD TV V V HD TV V V v cv n t ui KL0X14B LriKLAzo A21A22BKI A26A27VJA29X30 o A32-r>ri2,wherein:Xo is D or E, or is absent;Xi is A, L, V, I, S, E, R or K;X3 is Q, E or D;X7isA, L, V, I, S,R,EorD;Xl4 is Q, D, E, Aib, S or T;X20 is Q or E;X21 is D or E;X22 is Y, L or F;X26 is D or Q;X27 is V or S;X29 is S or A;X30 is G or E; andX32 is P or trans-Hyp.

2. The derivative or a pharmaceutically acceptable salt thereof of claim 1, wherein a combination of Xi and X7 is selected from A-A, L-L, V-V, I-I, S-S, A-S, S-A, E-R, R-E, R-D, K-E, K-D or E-E; and a combination of X29-X30 is selected from S-E, S-G, A-G or A-E3. The derivative or a pharmaceutically acceptable salt thereof of claim 1 or 2, wherein X3 is Q.

4. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein Xu is Q, D or E.

5. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein X20 is Q.

6. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein X21 is D.

7. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-6, wherein X22 is Y or L.

8. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-7, wherein a combination of X26 and X27 is selected from D-V, Q-S, Q-V, and D-S.

9. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein the combination of X29-X30 is S-G.

10. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein X32 is P.

11. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-4, comprising a polypeptide with an amino acid sequence of ASQLS TAVLG RLSX14E LHRLX20 DX22PRT DVGX29G SP-NH2, wherein,X14 is Q, D or E;X20 is Q or E, preferably Q;X22 is Y or L; andX29 is S or A.

12. The derivative or a pharmaceutically acceptable salt thereof of claim 11, comprising a polypeptide with an amino acid sequence of ASQLS TAVLG RLSX14E LHRLQ DX22PRT DVGSG SP-NH2, wherein,X14 is Q, D or E, preferably Q or D; andX22isYorL.

13. The derivative or a pharmaceutically acceptable salt thereof of claim 1, wherein the amino acid sequence is selected from any one of SEQ ID NO. 1-SEQ ID NO. 38.

14. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-8 or 10-13, wherein the sequence of the polypeptide is any one of:ASQLS TAVLG RLSDE LHRLQ DYPRT DVGSG SP-NH2,ASQLS TAVLG RLSQE LHRLQ DLPRT DVGSG SP-NH2,ASQLS TAVLG RLSEE LHRLQ DYPRT DVGSG SP-NH2,ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAG SP-NH2,ASQLS TAVLG RLSQE LHRLQ DYPRT DVGAE SP-NH2, orASQLS TAVLG RLSQE LHRLE DYPRT DVGSG SP-NH2.

15. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 1-14, wherein the derivative comprises a fatty acid-containing side chain linked to the N terminus of the polypeptide.

16. The derivative or a pharmaceutically acceptable salt thereof of claim 15, wherein the fatty acid-containing side chain is in the form of Z1+Z2+Z3, wherein Z1 is a C16-C22 fatty diacid;Z2 is selected from any one of yGlu, aGlu, PAsp, aAsp, Inp, and Trx, or is absent;Z3 is n AEEA(s), wherein n>0; andZl, Z2, and Z3 are linked via amide linkages.

17. The derivative or a pharmaceutically acceptable salt thereof of claim 16, wherein Zl is a C20 fatty diacid.

18. The derivative or a pharmaceutically acceptable salt thereof of claim 16 or 17, wherein Z2 is yGlu.

19. The derivative or a pharmaceutically acceptable salt thereof of any one of claims 16-18, wherein n is selected from 0, 1, 2, 3, 4, 5 or 6.

20. A polypeptide comprising an amino acid sequence of the derivative of any one of claims 1-14.

21. A pharmaceutical composition comprising the derivative of any one of claims 1-19 or the polypeptide of claim 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. Use of the derivative of any one of claims 1-19 or the polypeptide of claim 20, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing and / or treating overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain.

23. Use of the derivative of any one of claims 1-19 or the polypeptide of claim 20, or a pharmaceutically acceptable salt thereof, in reducing food intake.

24. A method of preventing and / or treating overweight and / or obesity and / or type I or type II diabetes and / or osteoporosis and / or neuropathic pain, comprising administering to a subject a prophylactically or therapeutically effective amount of thederivative of any one of claims 1-19 or the polypeptide of claim 20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21.

25. A method of reducing food intake, comprising administering to a subject an effective amount of the derivative of any one of claims 1-19 or the polypeptide of claim 20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 21.PCT / CN2024 / 085852A. CLASSIFICATION OF SUBJECT MATTERC07K14 / 585(2006.01)i; A61K38 / 23(2006.01)iAccording to International Patent Classification (IPC) or to both national classification and IPCB. FIELDS SEARCHEDMinimum documentation searched (classification system followed by classification symbols) IPC: C07K, A61KDocumentation searched other than minimum documentation to the extent that such documents are included in the fields searchedElectronic data base consulted during the international search (name of data base and, where practicable, search terms used)CNABS, CNTXT, EPTXT, JPTXT, TWTXT, USTXT, VEN, WOTXT, cnki, 7J 4, WANFANG, ncbi, 1¾ Baidu, Baidu Scholar, China Patent Biological Sequence Search System, blast, EBI, STN, Uniprot: ttil'l'lC. DOCUMENTS CONSIDERED TO BE RELEVANTCategory* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A CN 106957360 A (SECOND MILITARY MEDICAL UNIVERSITY OF PLA) 18 July 2017 (2017-07-18) description, paragraphs [0058]-[0060], table 2. and sequence listing, sequence 3 1-25 A CN 1235980 A (SHANGHAI INST. OF BIOCHEMISTRY, CHINESE ACADEMY OF SCIENCES) 24 November 1999 (1999-11-24) abstract, and claims 1-6 1-25 A CN 102911266 A (CHINESE PEPTIDE CO., LTD.) 06 February 2013 (2013-02-06) abstract, and claims 1-10 1-25 A CN 102924587 A (CHINESE PEPTIDE CO., LTD.) 13 February 2013 (2013-02-13) abstract, and claims 1-10 1-25| | Further documents are listed in the continuation of Box C.annex.* Special categories of cited documents: “T” later document published after the international filing date or priority “A” document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand the to be of particular relevance principle or theory underlying the invention “D” document cited by the applicant in die international application “X” document of particular relevance; the claimed invention cannot be “E" earlier application orpatent but published on or after the international considered novel or cannot be considered to involve an inventive step filing date when the document is taken alone •SL” document which may throw doubts on priority claim(s) or which is “Y” document of particular relevance; the claimed invention cannot be cited to establish the publication date of another citation or other considered to involve an inventive step when the document is special reason (as specified) combined with one or more other such documents, such combination “O” document referring to an oral disclosure, use, exhibition or other being obvious to a person skilled in the art means document member of the same patent family “P” document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search 16 June 2024 Date of mailing of the international search report 21 June 2024 Name and mailing address of the ISA / CN China National Intellectual Property Administration (ISA / CN) China No. 6, Xitucheng Road, Jimenqiao, Haidian District, Beijing 100088 Authorized officer Telephone No.INTERNATIONAL SEARCH REPORT International application No. PCT / CN2024 / 085852c.DOCUMENTS CONSIDERED TO BE RELEVANTCategory* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A (LI, Yanetal.). (Non-official Translation: The Role of Procalcitonin in Early Diagnosis and Prognosis of Hemorrhagic Fever with Renal Syndrome)" BBISSSsiS (Guide of China Medicine), Vol. 15, No. (35), 31 December 2017 (2017-12-31), pp. 62-63 1-25 A STIPANI, V. et al. "Channel Formation by Salmon and Human Calcitonin in Black Lipid Membranes" Biophysical Journal, Vol. 81, No. (6), 31 December 2001 (2001-12-31), pp. 3332-3338 1-25INTERNATIONAL SEARCH REPORT International application No. PCT / CN2024 / 085852 Box No. I Nucleotide and / or amino acid sequence(s) (Continuation of item l.c of the first sheet)1. With regard to any nucleotide and / or amino acid sequence disclosed in the international application, the international search was carried out on the basis of a sequence listing: a. / forming part of the international application as filed. b. __ furnished subsequent to the international filing date for the purposes of international search (Rule 13ter. 1(a)),accompanied by a statement to the effect that the sequence listing does not go beyond the disclosure in the international application as filed.

2. | | With regard to any nucleotide and / or amino acid sequence disclosed in the international application, this report has been established to the extent that a meaningful search could be carried out without a WIPO Standard ST.26 compliant sequence listing.

3. Additional comments:PCT / CN2024 / 085852Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

1. Pl Claims Nos.: 23-25because they relate to subject matter not required to be searched by this Authority, namely:Claims 23-25 relate to a method for treating a living human or animal body, which falls within the cases set out in PCT Rule 39.1 (iv) for which an international search is not required; however, a search is still conducted on the basis of a pharmaceutical use.

2. | | Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:3 U Claims Nos.:because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).INTERNATIONAL SEARCH REPORT Information on patent family membersInternational application No.PCT / CN2024 / 085852Patent document cited in search report Publication date (day / month / year) Patent family member)s) Publication date (day / month / year) CN 106957360 A 18 July 2017 None CN 1235980 A 24 November 1999 None CN 102911266 A 06 February 2013 None CN 102924587 A 13 February 2013 None

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