Lipolytic peptides

Abstract

The present invention provides a lipolytic peptide or a salt thereof having a sequence of 5 to 9 amino acids in length and corresponding to the sequence of SEQ ID NO: 54, wherein X 1 represents W or N; X 2 represents P, N, a basic amino acid, or a hydrophobic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; X 5 represents F or P; and the subscripts "a", "b", "c", "d", "e", "f" and "g" are integers independently selected from 0 and 1; with the proviso that two, three, four, five or six of the subscripts "a", "b", "c", "d", "e", "f" and "g" represent 1 and the remaining represent "0". The present invention further provides peptides of the sequences of SEQ ID NOs: 39-46 or any salt thereof. The peptides of the present invention exhibit improved lipolytic activity when compared to other lipolytic agents such as caffeine or Hexa-39. (T) a (X 1 ) b D(X 2 ) g EG(X 3 ) c (X 4 ) d (X 5 ) e (Y) f (SEQ ID NO:54)

Description

[Technical field]

[0001] This application claims the benefit of European Patent Application No. 21383114.2, filed December 3, 2021.

[0002] The present invention relates to the field of peptides and lipolysis. In particular, the present invention provides lipolytic peptides, compositions containing same, and their therapeutic and cosmetic uses, inter alia, as lipolytic agents. [Background technology]

[0003] Fat management in the human body is regulated by adipose tissue, and more specifically by the cells that populate this tissue, the adipocytes, and involves multiple cellular mechanisms, including those for storing fat and those for releasing, breaking down, and / or transforming fat.

[0004] In general, the metabolism of fat cells has a large impact on the overall metabolism of the human body. This excess can lead to obesity, which is called overweight. Currently, about 30% of the population is overweight or obese.

[0005] The state of the art describes plants that have an effect on adipose tissue.

[0006] In particular, coffee and tea have an effect on adipose tissue: these effects are mainly linked to the presence of caffeine in these plants, which, whether of natural or synthetic origin, is particularly involved in activating lipolysis and in the general stimulation of the metabolism of adipocytes.

[0007] However, it is difficult to control the daily intake of caffeine, especially since this molecule is present in many foods. Accurate monitoring is difficult, if not impossible. Furthermore, caffeine has effects on other metabolic processes in humans, apart from its effects on adipose tissue. In general, caffeine is known to be a stimulant and psychostimulant. It has effects on the cardiovascular system and can cause harmful acceleration of the heart rate. In some cases, caffeine has a diuretic effect. It is also an antagonist of the receptors of the neurotransmitter adenosine in the central nervous system. Therefore, caffeine can cause physical and psychological dependence in some people.

[0008] Apart from adrenergic substances (adrenaline and its analogues) that are known for their activity of stimulating lipolysis in adipocytes but are prohibited for use in cosmetics, small peptides have also been developed.For example, WO2012130775 discloses small peptides that regulate the expression of coactivator PGC-lct.Among these peptides, a peptide known as "acetyl-hexapeptide-39" is disclosed.

[0009] However, despite these efforts, there remains a need for small peptides that have improved profiles, are easier to synthesize, and are safer. Summary of the Invention

[0010] The present inventors have developed short peptides having 5-9 amino acids that have significant lipolytic activity when tested in vitro.

[0011] As explained above, caffeine is one of the most widely used lipolytic agents. However, caffeine is a stimulant and has negative effects on some metabolic processes, such as harmful acceleration of heart rate or addiction.

[0012] The inventors have found that the peptides of the invention, even with their short length, are surprisingly more active than caffeine: as shown in Table 6a below, the peptides of the invention show a significant increase in lipolytic activity at concentrations that are comparable to or significantly lower (i.e. 2-fold, 10-fold or 100-fold lower) than those of caffeine.

[0013] This was found in mouse adipocytes, but was also confirmed using human adipocytes, as shown in Table 6b.

[0014] The inventors have also found that the D-decapeptide of sequence SEQ ID NO: 3, optionally derivatized at the N-terminus and / or C-terminus (SEQ ID NO: 4-6), has a significant lipolytic activity. The inventors found that this D-decapeptide exhibits an approximately two-fold increase in lipolytic activity when compared to the L-form. This finding was surprising, since the test conditions followed to determine the lipolytic activity allowed the inventors to conclude that such a significant improvement in activity was not due to a "stability" effect (no test conditions were used that would affect such properties).

[0015] Moreover, the inventors have surprisingly found that the D-decapeptide of sequence SEQ ID NO:3 provides such improved lipolysis activity significantly faster when compared to the corresponding L-form (SEQ ID NO:2). As can be derived from Table 7 below, the peptide of the invention provided a significant amount of glycerol at 120 minutes, indicating a lipolysis effect. In contrast, neither caffeine nor the comparative peptide (L-form) at the same dose showed any significant activity at that time point. On the other hand, Table 7 again highlights the improved efficiency of inducing lipolysis when using the peptide of the invention, even after a very short time after administration. In this case, peptide SEQ ID NO:3 was found to be more than 24 times more efficient at 120 minutes and more than 5 times more efficient at 240 minutes, compared to caffeine or SEQ ID NO:2.

[0016] In conclusion, the peptides of the present invention not only provide lipolytic activity more efficiently, but also (1) induce the onset of lipolytic activity significantly earlier, and (2) sustain the lipolytic effect for a longer period of time.

[0017] Furthermore, the small size of the peptides of the invention facilitates their synthesis on an industrial scale.

[0018] Advantageously, due to such improved properties, the peptides of the present invention can be used in lower doses, avoiding all or some of the negative effects associated with the use of higher doses of caffeine.

[0019] Thus, in one aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: (a) having a sequence of 5 to 9 amino acids in length, each amino acid being either an L-amino acid or a D-amino acid, the peptide corresponding to the sequence of SEQ ID NO: 54, or an acceptable salt thereof: (T) a (X 1 ) b D(X 2 ) g EG(X 3 ) c (X 4 ) d (X 5 ) e (Y) f During the ceremony: X 1 represents W, N, Q or K; X 2 represents P, N, a basic amino acid, or a hydrophobic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; X 5 represents F or P, the subscripts "a", "b", "c", "d", "e", "f" and "g" are integers independently selected from 0 and 1; provided that two, three, four, five or six of the subscripts "a", "b", "c", "d", "e", "f" and "g" represent 1 and the remaining subscripts represent 0; or, (b) a lipolytic peptide selected from the group consisting of SEQ ID NOs: 39-46, and any salts thereof; The N-terminus of the lipolytic peptide is -NR 1 R 2 Corresponding to R 1 and R 2 -H, -C(O)R 3 , triglycerides and (C 1 ~C 20 ) alkyl; The C-terminus of the lipolytic peptide is -COOR 4 and -C(O)NR 5 R 6 Corresponding to; R 3 ~R 6 is -H and (C 1 ~C 20 ) alkyl.

[0020] The data presented in Table 6b below also show that the short peptides of the invention are highly effective when compared to hexapeptide-39 (SEQ ID NO: 53). In particular, they were found to provide at least about a 40% increase in lipolytic effect on human adipocytes compared to hexapeptide-39.

[0021] In a second aspect, the present invention provides a cosmetic composition comprising a cosmetically effective amount of a peptide as defined in the first aspect of the invention, or a salt thereof, together with one or more cosmetically acceptable carriers or excipients.

[0022] These compositions of the present invention may also provide additional advantages including stability, lack of significant (consumer unacceptable) skin irritation, superior aesthetics, or improved skin diffusion, among others.

[0023] In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a peptide as defined in the first aspect of the invention, or a salt thereof, together with one or more therapeutically acceptable carriers or excipients.

[0024] In a fourth aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (a) a peptide as defined in the first aspect of the invention, or a composition as defined in the second or third aspect of the invention, (b) an injection device, e.g., a device selected from the group consisting of a syringe, one or more microneedles, an implant, or a biodegradable container, wherein the kit comprises the peptide or composition physically separated from the device.

[0025] In a fifth aspect, the present invention provides the use of a peptide as defined in the first aspect of the invention as a lipolytic agent.

[0026] The peptide of the present invention, due to its role as a lipolytic agent, can be used to reduce lipid (adipose tissue mass) accumulation in many parts of the animal body. In particular, in the human body, fat deposits (adipose tissue containing large amounts of triglycerides) tend to accumulate in the hips, waist, abdomen, and thighs.

[0027] In a sixth aspect, the present invention provides the use of a peptide as defined in the first aspect of the invention, or a cosmetic composition as defined in the second aspect of the invention, in a cosmetic product.

[0028] In a seventh aspect, the present invention provides the use of a cosmetically effective amount of a peptide as defined in the first aspect of the present invention or a cosmetic composition as defined in the second aspect of the present invention in improving the physical appearance of a mammal having subcutaneous fat herniated or accumulated in fibrous connective tissue beneath the skin. This aspect may alternatively be formulated as a cosmetic method for improving the physical appearance of a mammal having subcutaneous fat herniated or accumulated in fibrous connective tissue beneath the skin, the method comprising applying, in particular topically or intradermally, to a subject a peptide as defined in the first aspect of the present invention or a cosmetic composition as defined in the second aspect of the present invention.

[0029] In a further aspect, the present invention provides a peptide as defined in the first aspect of the invention or a pharmaceutical composition according to the third aspect of the invention for use in therapy.

[0030] In a final aspect, the present invention provides a peptide as defined in the first aspect of the invention or a pharmaceutical composition as defined in the third aspect of the invention for use in treating visceral fat accumulation. This aspect may be described as the use of a peptide as defined in the first aspect of the invention or a pharmaceutical composition as defined in the third aspect of the invention for the manufacture of a medicament for treating visceral fat accumulation. This aspect may also be described as a method of treating visceral fat accumulation, the method comprising administering a therapeutically effective amount of a peptide as defined in the first aspect of the invention or a pharmaceutical composition as defined in the third aspect of the invention to a subject in need thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] All terms used herein in this application are to be understood with their ordinary meaning known in the art unless otherwise specified. Other more specific definitions of certain terms used in this application are as follows, and are intended to be applied uniformly throughout the specification and claims, unless a definition expressly stated otherwise provides a broader definition.

[0032] For purposes of the present invention, any range given includes both the lower and upper endpoints of the range.

[0033] The present inventors provide a peptide or a salt thereof useful as a lipolytic agent, as provided in a first aspect of the present invention.

[0034] In the present invention, "amino acid" refers to a molecule that contains both an amino group and a carboxyl group.

[0035] Basic amino acids (hereinafter also referred to as "basic polar amino acids") have nitrogen-containing side chains and are similar to the base ammonia (such as amines, guanidines, or imidazoles). Their pKa is high enough that they tend to combine with protons, acquiring a positive charge in the process. Non-limiting examples of basic amino acids are Lys, Arg, and His.

[0036] The term "hydrophobic amino acid" as used herein refers to an amino acid having a hydrophobic side chain that tends to be repelled by water. When these amino acids are part of a protein, they typically form the hydrophobic core of the protein that is isolated from polar solvents. Non-limiting examples of hydrophobic amino acids include glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), methionine (Met), and tryptophan (Trp). In certain embodiments, the hydrophobic amino acid referred to herein is selected from the list consisting of glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), methionine (Met), and tryptophan (Trp). In another embodiment, the hydrophobic amino acids referred to herein are selected from the list consisting of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe) and cysteine ​​(Cys). In a particular embodiment, the hydrophobic amino acids referred to herein are selected from the list consisting of alanine (Ala), valine (Val), and leucine (Leu). The amino acids used in the construction of the peptides of the invention may be prepared by organic synthesis or may be obtained by other routes, such as, for example, degradation or isolation from natural sources.

[0037] As used herein, the term "acceptable salt" or "salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the normal scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Suitable acceptable salts are well known in the art. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, sphagocytate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lanthanide, and tetrahydrofuran. Examples of suitable salts include carbohydrazide, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, and ammonium. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.Further acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.

[0038] (C 1 ~C 20 The term (C) alkyl refers to a saturated linear or branched alkyl chain having 1 to 20 carbon atoms. 1 ~C 15 ) alkyl and (C 1 ~C 10 ) The term alkyl refers to saturated straight or branched alkyl chains having 1 to 15 carbon atoms, or 1 to 10 carbon atoms, respectively.

[0039] The terms "D amino acid", "D-aa" or "Daa" (wherein amino acid (aa) can be any amino acid mentioned herein) refer to amino acids having a D configuration that is well known to those skilled in the art.

[0040] The terms "L-amino acid", "L-aa" or "Laa" (wherein amino acid (aa) can be any amino acid mentioned herein) refer to amino acids having the L-configuration that are well known to those skilled in the art.

[0041] Unless otherwise specified, one or more of the amino acids forming the peptides of the present invention may have the L- or D-configuration.

[0042] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, at least one of the amino acids forming the peptide of sequence SEQ ID NO: 54 is a D-amino acid. In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, one, two, three, four, five, six, seven, eight, nine or all of the amino acids forming the peptide of sequence SEQ ID NO: 54 are D-amino acids. In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, all of the amino acids forming the peptide of sequence SEQ ID NO: 54 are D-amino acids. In an embodiment of the first aspect of the invention, in the peptide of the first aspect of the invention, preferably in the peptide of SEQ ID NO: 54, the amino acids that are not D-amino acids are L-amino acids. In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, all of the amino acids forming the peptide of sequence SEQ ID NO: 54 are L-amino acids.

[0043] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, at least one of the amino acids forming the peptide of sequence SEQ ID NO:1 is a D-amino acid. In another embodiment of the first or second aspect of the invention, optionally in combination with any of the above or below embodiments, one, two, three, four, five, six, seven, eight, nine or all of the amino acids forming the peptide of sequence SEQ ID NO:1 are D-amino acids. In another embodiment of the first or second aspect of the invention, optionally in combination with any of the above or below embodiments, all of the amino acids forming the peptide of sequence SEQ ID NO:1 are D-amino acids. In an embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the amino acids in the peptide of sequence SEQ ID NO:1 that are not D-amino acids are L-amino acids. In another embodiment of the first or second aspect of the invention, optionally in combination with any of the above or below embodiments, all of the amino acids forming the peptide of sequence SEQ ID NO:1 are L-amino acids.

[0044] In one embodiment of the first aspect of the invention, the lipolytic peptide is selected from the sequences of SEQ ID NO: 39-46 and salts thereof, wherein one, two, three, four, five, six, seven, eight, nine or all amino acids are D-amino acids. In one embodiment of the first aspect of the invention, the lipolytic peptide is selected from the sequences of SEQ ID NO: 39-46 and salts thereof, wherein all amino acids are D-amino acids. In an embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the amino acids in the peptides of sequences SEQ ID NO: 39-46 that are not D-amino acids are L-amino acids. In another embodiment of the first or second aspect of the invention, optionally in combination with any of the above or below embodiments, all amino acids forming the peptides of sequences SEQ ID NO: 43-46 are L-amino acids.

[0045] In an embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9 or all amino acids of the lipolytic peptide of the invention are D-amino acids. In a particular embodiment of the first aspect of the invention, all amino acids of the lipolytic peptide of the invention are D-amino acids.

[0046] In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54, as defined above, or a salt thereof, wherein X 2 represents P, N, or a basic amino acid, The subscript "g" stands for 1, X 5 represents F, The peptide corresponds to the peptide of sequence SEQ ID NO:1.

[0047] As will be well understood by those skilled in the art, one, two, three, four or five of the subscripts "a", "b", "c", "d", "e", "f" of the lipolytic peptides defined in the above embodiments represent 1 and the remaining subscripts represent 0.

[0048] Thus, in a particular embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide having a sequence of 5 to 9 amino acids in length (wherein each amino acid is either an L-amino acid or a D-amino acid) corresponds to the sequence of SEQ ID NO: 1 or a salt thereof: (T) a (X 1 ) b D(X 2 )EG(X 3 ) c (X 4 ) d (F) e (Y) f During the ceremony: X 1 represents W, N, Q or K; X 2 represents P, N, or a basic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; The subscripts "a", "b", "c", "d", "e", and "f" are integers independently selected from 0 and 1, with the proviso that 1, 2, 3, 4, or 5 of the subscripts "a", "b", "c", "d", "e", and "f" represent 1 and the remaining subscripts represent 0.

[0049] Thus, in a particular embodiment of the first aspect of the invention, the lipolytic peptide of the invention comprises: (a) having a sequence of 5 to 9 amino acids in length, each amino acid being either an L-amino acid or a D-amino acid, the peptide corresponding to the sequence of SEQ ID NO: 1 or an acceptable salt thereof: (T) a (X 1 ) bD(X 2 )EG(X 3 ) c (X 4 ) d (F) e (Y) f During the ceremony: X 1 represents W, N, Q or K; X 2 represents P, N, or a basic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; the subscripts "a", "b", "c", "d", "e", and "f" are integers independently selected from 0 and 1, with the proviso that 1, 2, 3, 4, or 5 of the subscripts "a", "b", "c", "d", "e", and "f" represent 1 and the remaining subscripts represent 0; or, (b) selected from the group consisting of SEQ ID NOs: 39-46, and any salt thereof; The N-terminus of the lipolytic peptide is -NR 1 R 2 Corresponding to R 1 and R 2 -H, -C(O)R 3 , triglycerides and (C 1 ~C 20 ) alkyl; The C-terminus of the lipolytic peptide is -COOR 4 and -C(O)NR 5 R 6 Corresponding to; R 3 ~R 6 is -H and (C 1 ~C 20 ) alkyl.

[0050] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is provided as a peptide of sequence SEQ ID NO: 1, as defined above, or a salt thereof, wherein X 1 stands for W or N; in particular, X 1 represents a D-amino acid selected from DW or DN. In a particular embodiment, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1 as defined above, or a salt thereof, wherein X 1 stands for W, especially X 1 represents a D-amino acid and is DW. In another particular embodiment, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1, as defined above, or a salt thereof, wherein X 1 stands for N, especially X 1 represents a D-amino acid, DN.

[0051] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1, as defined above, or a salt thereof, wherein X 2 stands for W or N; in particular, X 2 represents a D-amino acid selected from DP or DN.

[0052] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1, as defined above, or a salt thereof, wherein X 3 and X 4 are the same or different and represent V, L or I; in particular X 3 and X 4 are the same or different D-amino acids and represent DV, DL or DI. In another embodiment of the first aspect of the invention, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1, or a salt thereof, wherein X 3 represents V, L or I, in particular X 3represents a D-amino acid selected from DV, DL and DI. In another embodiment of the first aspect of the invention, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1, or a salt thereof, wherein X 4 represents V, L or I, in particular X 4 represents a D-amino acid selected from DV, DL and DI.

[0053] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1 or a salt thereof, composed of L- and / or D-amino acids as defined above, which are selected from the sequences SEQ ID NO: 47 to SEQ ID NO: 49 and any salts thereof: SEQ ID NO:47(T) a (X 1 ) b DPEGV(X 4 ) d (F) e (Y) f , where "a", "b", "d", "e", and "f" are as defined in claim 1; and X 1 represents W or N, and X 4 represents I or L; SEQ ID NO:48(T) a (X 1 ) b DPEGX 3 (F) e (Y) f , where "a", "b", "e" and "f" are as defined in claim 1; and X 1 represents W or N, and X 3 represents I or L; SEQ ID NO:49(T) a (W) b DNEG(X 3 )(F) e (Y) f , where "a", "b", "e" and "f" are as defined in claim 1; and X 3 represents I or L, in particular L.

[0054] In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1 or a salt thereof, composed of L- and / or D-amino acids as defined above, which is represented by SEQ ID NO: 73 and any salts thereof: SEQ ID NO: 73NDPEG(L) c Y, where "c" is as defined above in SEQ ID NO:1 and claim 1.

[0055] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1 as defined above or a salt thereof, which is composed of L-amino acids and / or D-amino acids, which are selected from the group consisting of sequences SEQ ID NO: 47 to SEQ ID NO: 49 and SEQ ID NO: 73, wherein the sequence has one or more D-amino acids. In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 1 as defined above or a salt thereof, which is selected from the group consisting of sequences SEQ ID NO: 50 to SEQ ID NO: 52 and SEQ ID NO: 77. As will be well understood by the skilled person, SEQ ID NO: 50 to SEQ ID NO: 52 have the same amino acid sequence as SEQ ID NO: 47 to SEQ ID NO: 49, respectively, but each amino acid in each sequence is a D-amino acid.

[0056] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54, as defined above, or a salt thereof, wherein X 1 stands for N, especially X 1 stands for D-amino acid, DN.

[0057] In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54, as defined above, or a salt thereof, wherein X 2stands for P, L, V, or A, and especially X 2 is a D-amino acid, and represents DP, DL, DV, or DA.

[0058] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54, as defined above, or a salt thereof, wherein X 3 and X 4 are the same or different and represent V, L or A; in particular X 3 and X 4 are the same or different D-amino acids and represent DV, DL or DA. In another particular embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54, as defined above, or a salt thereof, wherein X 3 represents V, L or A, and in particular X 3 In another particular embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54, as defined above, or a salt thereof, in which X 4 represents V, L or A, and in particular X 4 is a D-amino acid, representing DV, DL or DA.

[0059] In another embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54, as defined above, or a salt thereof, wherein X 5 represents P or F, in particular, X 5 is a D-amino acid, and represents DP or DF.

[0060] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54 as defined above, or a salt thereof, which, as described above, is composed of D-amino acids and / or D-amino acids, which are selected from the group consisting of sequences SEQ ID NO: 72, 73, 74 and 75 and any salts thereof, preferably selected from the group consisting of sequences SEQ ID NO: 72, 74 and 75 and any salts thereof: SEQ ID NO: 72 ND(X 2 ) g EG(X 3 ) c (X 5 ) e Y, where "g", "c" and "e" are as defined above for SEQ ID NO:54 and in claim 1; 2 represents V, A, L, or P, and X 3 stands for L, V, or A, and X 5 represents P or F. SEQ ID NO:73 NDPEG(L) c Y, where "c" is as defined above in SEQ ID NO:54 or SEQ ID NO:1 and claim 1. SEQ ID NO: 74 ND(X 2 ) g (X 3 ) c (X 5 ) e Y, where "c", "e" and "g" are as defined above for SEQ ID NO:54 and in claim 1; 2 represents V, A or L, and X 3 represents L, V, A, and X 5 represents F or P. Sequence number 75ND(X 2 ) g EGLY, where "g" is as defined above for SEQ ID NO:54 and claim 1; and X 2 is P or L.

[0061] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54 as defined above, or a salt thereof, which is selected from the group consisting of sequences SEQ ID NO: 72 to SEQ ID NO: 75, preferably SEQ ID NO: 72, SEQ ID NO: 74 and SEQ ID NO: 75, wherein the sequence has one or more D-amino acids. In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the lipolytic peptide is a peptide of sequence SEQ ID NO: 54 as defined above, or a salt thereof, which is selected from the group consisting of sequences SEQ ID NO: 76 to SEQ ID NO: 79, preferably SEQ ID NO: 76, 78 and 79. As will be well understood by the skilled person, SEQ ID NO: 76 to 79 have the same amino acid sequence as SEQ ID NO: 72 to 75, respectively, but each amino acid in each sequence is a D-amino acid.

[0062] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the N-terminus of the lipolytic peptide of the invention is -NH 2 or -NHC(O)R 3 Corresponding to R 3 is (C 1 ~C 20 ) alkyl, especially (C 1 ~C 15 ) alkyl, more particularly (C 1 ~C 10 ) alkyl. In a particular embodiment, the N-terminus of the lipolytic peptide of the present invention is -NH 2 In a particular embodiment, the N-terminus of the lipolytic peptide of the invention corresponds to -NHC(O)R 3 Corresponding to R 3 is (C 1 ~C 20 ) alkyl, preferably R 3 is (C 1 ~C 15 ) alkyl, more preferably R 3 is (C 1 ~C 10 ) alkyl.

[0063] In another particular embodiment, the N-terminus of the lipolytic peptide of the present invention is -NHC(O)R 3 Corresponding to R 3 is -CH 3 In another particular embodiment, the N-terminus of the lipolytic peptide of the present invention is -NHC(O)R 3 Corresponding to R 3 is CH 3 CH 2 In another particular embodiment, the N-terminus of the lipolytic peptide of the invention corresponds to -NHC(O)R3, where R 3 is CH 3 (CH 2 ) 14 It is.

[0064] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the C-terminus of the lipolytic peptide is -COOH, -C(O)NH 2 or -C(O)NHR 6 where R 6 is (C 1 ~C 20 In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the C-terminus of the lipolytic peptide is -COOH or -C(O)NH 2 It is.

[0065] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the N-terminus of the lipolytic peptide of the invention is -NH 2 or -NHC(O)R 3 Corresponding to R 3 is (C 1 ~C 10 ) alkyl; the C-terminus of the lipolytic peptide is -COOH or -C(O)NH 2 It is.

[0066] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the N-terminus of the lipolytic peptide of the invention is -NH 2The C-terminus of the lipolytic peptide corresponds to -COOH, -C(O)NH 2 or -C(O)NHR 6 where R 6 is (C 1 ~C 20 ) alkyl, and preferably the C-terminus of the lipolytic peptide is -COOH or -C(O)NH 2 It is.

[0067] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the N-terminus of the lipolytic peptide of the invention is -NHC(O)R 3 Corresponding to R 3 is (C 1 ~C 20 ) alkyl, preferably R 3 is (C 1 ~C 15 ) alkyl; more preferably R 3 is (C 1 ~C 10 ) alkyl; the C-terminus of the lipolytic peptide is -COOH, -C(O)NH 2 or -C(O)NHR 6 where R 6 is (C 1 ~C 20 ) alkyl, and preferably the C-terminus of the lipolytic peptide is -COOH or -C(O)NH 2 It is.

[0068] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the N-terminus of the lipolytic peptide of the invention is -NHC(O)R 3 Corresponding to R 3 -CH 3 and the C-terminus of the lipolytic peptide is -COOH, -C(O)NH 2 or -C(O)NHR 6 where R 6 is (C 1 ~C 20 ) alkyl, and preferably the C-terminus of the lipolytic peptide is -COOH or -C(O)NH2 It is.

[0069] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the N-terminus of the lipolytic peptide of the invention is -NHC(O)R 3 Corresponding to R 3 is CH 3 CH 2 and the C-terminus of the lipolytic peptide is -COOH, -C(O)NH 2 or -C(O)NHR 6 where R 6 is (C 1 ~C 20 ) alkyl, and preferably the C-terminus of the lipolytic peptide is -COOH or -C(O)NH 2 It is.

[0070] In one embodiment of the first aspect of the invention, optionally in combination with any of the above or below embodiments, the N-terminus of the lipolytic peptide of the invention is -NHC(O)R 3 Corresponding to R 3 is CH 3 (CH 2 ) 14 and the C-terminus of the lipolytic peptide is -COOH, -C(O)NH 2 or -C(O)NHR 6 where R 6 is (C 1 ~C 20 ) alkyl, and preferably the C-terminus of the lipolytic peptide is -COOH or -C(O)NH 2 It is.

[0071] In another embodiment of the first aspect of the present invention, the peptide or salt thereof is selected from the group consisting of SEQ ID NOs: 3-38, 55-71, 80-87, and any salts thereof.

[0072] In another embodiment of the first aspect of the present invention, the peptide or salt thereof is selected from the group consisting of SEQ ID NOs: 3-38, 61, 66, 69, 80-87, and any salts thereof.

[0073] In another embodiment of the first aspect of the present invention, the peptide or salt thereof is selected from the group consisting of SEQ ID NOs: 55-60, 62-65, 67, 68, 70 and 71, and any salts thereof.

[0074] The second and third aspects of the present invention provide cosmetic and pharmaceutical compositions, respectively.

[0075] The compositions of the present invention may also include one or more additional lipolytic agent(s).

[0076] "Lipolytic agent" in the context of the present invention is understood as a compound that induces lipolysis, which enzymatically breaks down triglycerides into glycerol and fatty acids.Non-limiting examples of further lipolytic agents are phosphodiesterase inhibitors (e.g., xanthine derivatives), alpha 2 blocker compounds that can block alpha 2 receptors on the surface of fat cells, beta adrenergic agonists and antagonists (e.g., alverine and its organic or inorganic salts, e.g., alverine citrate), agents that inhibit the synthesis of LDL and VLDL receptors, inhibitors of fatty acid synthesis enzymes such as acetyl-CoA carboxylase or fatty acid synthase or cerulenin, compounds that stimulate beta receptors and / or G proteins, glucose transport blockers such as cerulenin or rutin, neuropeptide Y (NPY) antagonists that can block NPY receptors on the surface of fat cells, cAMP and its cosmetically acceptable derivatives, adenylate cyclase enzyme activators such as forskolin, agents that modify fatty acid transport, peptides or proteins such as lipolytic peptides and lipolytic proteins, for example peptides derived from parathyroid hormone.

[0077] Other examples of lipolytic agents that can be used include plant extracts and marine extracts. Among the plant extracts, English ivy (Hedera helix), Chinese toro wax (Bupleurum chinensis), arnica (Arnica Montana L), rosemary (Rosmarinus officinalis N), marigold (Calendula officinalis), sage (Salvia officinalis L), ginseng (Panax ginseng), ginkgo, St. John's wort (Hyperycum Perforatum), butcher's broom (Ruscus aculeatus L), meadowsweet (Filipendula ulmaria L), big-flowered Jarva tea (Orthosiphon Stamincus Benth), algae (Fucus Vesiculosus), birch (Betula alba), green tea, cola nut (Cola Nipida), horse chestnut, bamboo, spade leaf (Centella asiatica, extracts of heather, fucus, willow, mouse-ear, extracts of escine, extracts of cangzhu, extracts of chrysanthellum indicum, extracts of plants of the Armeniacea genus, Atractylodis Platicodon, Sinnomenum, Pharbitidis, Flemingia, Coleus, e.g. Coleus forskohlii, Coleus blumei, Coleus esquirolii, Coleus scutellaroides, Coleus xanthos,Particular mention may be made of extracts of C. xanthantus and Coleus barbatus, such as the root extract of Coleus barbatus, Ballote, Guioa, Davallia, Terminalia, Barringtonia, Trema, antirobia, cecropia, argania, Dioscoreae, such as Dioscorea opposita or Mexican extracts, extracts of marine origin: algae or phytoplankton, such as Laminaria digitata extract, diatoms, extracts of rhodysterol. Naturally, all these extracts can be taken in mixtures.

[0078] The compositions according to the invention may also contain one or more additional active substances selected from among natural flavonoids, ruscogenin, esculoside, escin, nicotinate, heperidin methyl chalcone, butcher's broom, lavender or rosemary essential oils, agents acting on the microcirculation (vasoprotectants or vasodilators), such as extracts of Ammi visnaga; extracts of Centella asiatica and Siegesbeckia, silicon, amadoline, ergothioneine and its derivatives, hydroxystilbene and its derivatives (e.g. resveratrol), extracts of plants from the Ericaceae family, in particular bilberry extract (lowbush blueberry, Vaccinium angustifollium), vitamin C and its derivatives, retinol and its derivatives, and sunscreens of any nature.

[0079] The compositions of the present invention may include a variety of additional ingredients that may be active, functional, or otherwise conventionally used in cosmetics, personal care, or topical / transdermal products, etc. Of course, the decision to include or not include additional ingredients, and the selection of particular additional ingredients, will depend on the particular application and product formulation.

[0080] Therefore, the composition of the present invention may comprise at least one skin care active.As used herein, "skin care active" refers to an additional component that provides some benefit to the purpose of the composition.Such additional component may comprise, but is not limited to, one or more of cleaning agents, hair conditioning agents, skin conditioning agents, hair styling agents, antidandruff agents, hair growth promoters, fragrances, sunscreens and / or sun protection compounds, pigments, moisturizers, film formers, hair colorants, makeup agents, detergents, thickeners, emulsifiers, moisturizers, emollients, preservatives, deodorant actives, dermatologically acceptable carriers and surfactants.

[0081] The term "cosmetic composition" according to the present invention relates to a formulation that can be used for cosmetic purposes, as a basis for delivering one or more cosmetic ingredients.

[0082] The term "cosmetically acceptable" refers to an excipient or carrier that is suitable for use in contact with human skin without causing, inter alia, undue allergic response, instability, incompatibility, or toxicity.

[0083] Cosmetic compositions encompass the use of a cosmetically effective amount of the peptide(s) of the present invention in a mammal, which is typically lower than the therapeutically effective amount used when SHBG is used as a pharmaceutical.

[0084] As used herein, the term "SHBG" or "sex hormone binding globulin" refers to a protein encoded by a gene with gene ID 6462 in NCBI (version 6 Nov 2022).

[0085] In one embodiment, the cosmetic composition is a topical composition.

[0086] To increase the skin diffusion ability of a peptide and thus to be topically active, it is advantageous to render the peptide more lipophilic by grafting a longer or shorter chain fatty acid (lipoyl, myristyl, palmityl, stearyl, etc.) to the N-terminal residue of the peptide and / or esterifying the carboxyl groups of the peptide, using protocols routinely used by those skilled in the art.

[0087] The topical cosmetic composition comprises a cosmetic excipient or carrier suitable for topical administration, including, but not limited to, a skin barrier function repairing agent, a hydrating agent, an emollient, an emulsifier, a thickener, a moisturizing agent, a pH adjusting agent, an antioxidant, a preservative, a vehicle, or a mixture thereof. The excipient or carrier used is compatible with the skin, well tolerated, stable, and used in an amount sufficient to provide the desired consistency and easy application.

[0088] Examples of suitable topical skin barrier restoration agents include, but are not limited to, ceramides, cholesterol, fatty acids, and precursors of these lipids including cerebrosides, sphingoid bases such as phytosphingosine or sphingosine, or phospholipids including phosphatidylcholine, and agents that promote the synthesis of epidermal lipids such as urea, dexpanthenol, and alpha hydroxy acids including lactic acid.

[0089] Examples of suitable topical hydrating agents include, but are not limited to, collagen, collagen amino acids, dimethiconol, glycine, hyaluronic acid, dimethylsilanol hyaluronic acid, magnesium stearate, maltitol, maltose, pyrrolidone carboxylic acid (PCA), manganese PCA, sodium PCA, mannitol, trehalose, trilactin, glucose, glutamic acid, hydrolyzed caesalpinia spinosa gum, caesalpinia spinosa gum, prunus persica extract, prunus serotina extract, echinacea angustifolia extract, echinacea purpurea extract, methyl gluceth, hydrolyzed wheat gluten, erythritol, aluminum stearoyl glutamate, copper acetyl methionate, or ditridecyl dimmer dilinoleate. In particular, the hydrating agent is selected from the group consisting of glucose, glycine, lysine, glutamic acid, hydrolyzed Caesalpinia spinosa gum, Caesalpinia spinosa gum, sodium PCA, and mixtures thereof.

[0090] Examples of suitable topical emollients include, but are not limited to, octyl hydroxystearate, lanolin, caprylic / capric triglyceride, cetyl palmitate, octyldodecanol, cetyl alcohol, isopropyl isostearate, glyceryl dilaurate, isopropyl myristate, palm alcohol, dimethicone, squalane, Pulkenetia volubilis seed oil, butyrospermum parkii butter, sucrose cocoate, or mixtures thereof. In particular, the emollient is selected from the group consisting of dimethicone, squalane, Pulkenetia volubilis seed oil, butyrospermum parkii butter, caprylic / capric triglyceride, octyldodecanol, or mixtures thereof.

[0091] Examples of suitable emulsifiers include, but are not limited to, glyceryl trioleate, glyceryl oleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene monostearate, glycerol monooleate, sucrose distearate, polyethylene glycol monostearate, octylphenoxypoly(ethyleneoxy)ethanol, deacylpentaisostearate, sorbitan sesquioleate, hydroxylanolin, lecithin, lanolin, triglyceryl diisostearate, polyoxyethylene oleyl esters, and the like. ester, calcium stearoyl-2-lactylate, sodium lauroyl lactylate, sodium stearoyl lactylate, cetearyl glucoside, methyl glucoside sesquistearate, sorbitan monopalmitate, methoxypolyethylene glycol-22 / dodecyl glycol copolymer, polyethylene glycol-45 / dodecyl glycol copolymer, polyethylene glycol 400 distearate and glyceryl stearate, candelilla / jojoba / rice bran polyglyceryl-3 ester, cetyl phosphate, potassium cetyl phosphate, or mixtures thereof. In particular, the emulsifier is selected from the group consisting of glyceryl oleate, lecithin, sodium lauroyl lactylate, sodium stearoyl lactylate, glyceryl stearate, candelilla / jojoba / rice bran polyglyceryl-3 ester, and mixtures thereof.

[0092] Examples of suitable surfactants include, but are not limited to, nonionic, ionic (either anionic or cationic), or zwitterionic (or the head of the surfactant contains two oppositely charged groups) surfactants. Examples of anionic surfactants include, but are not limited to, those based on sulfate, sulfonate, or carboxylate anions, such as perfluorooctanoic acid (PFOA or PFO), alkylbenzene sulfonates, soaps, fatty acid salts, or alkyl sulfates, such as perfluorooctane sulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, or sodium lauryl ether sulfate (SLES). Examples of cationic surfactants include, but are not limited to, those based on quaternary ammonium cations such as cetyltrimethylammonium bromide (CTAB), also known as hexadecyltrimethylammonium bromide, cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), or alkyltrimethylammonium such as benzethonium chloride (BZT). Examples of zwitterionic surfactants include, but are not limited to, dodecyl betaine, cocamidopropyl betaine, or coco ampho glycinate. Examples of non-ionic surfactants include, but are not limited to, alkyl poly(ethylene oxide), alkylphenol poly(ethylene oxide), copolymers of poly(ethylene oxide), poly(propylene oxide) (trade names poloxamer or poloxamine), alkyl polyglucosides including octyl glucoside and decyl maltoside, fatty alcohols including cetyl alcohol and oleyl alcohol, cocamide MEA, cocamide DEA, or polysorbates such as Tween 20, Tween 80, or dodecyl dimethylamine oxide.In particular, surfactants that are foaming and skin-friendly include polysorbate 20 or 40, coco glucoside, lauryl glucoside, decyl glucoside, lauryl sulfate, such as ammonium, sodium, magnesium, MEA, triethylamine (TEA), or miparauryl sulfate, cocamidopropyl betaine, or sodium alkyl sulfosuccinate.

[0093] Examples of suitable topical moisturizers include, but are not limited to, glycerin, diglycerin, ethylhexylglycerin, glucose, honey, lactic acid, polyethylene glycol, propylene glycol, sorbitol, sucrose, or trehalose. In particular, the moisturizer is selected from the group consisting of glycerin, diglycerin, ethylhexylglycerin, and mixtures thereof.

[0094] Examples of suitable topical pH adjusters include, but are not limited to, acetic acid, lactic acid, citric acid, ethanolamine, formic acid, oxalic acid, potassium hydroxide, sodium hydroxide, triethanolamine, or mixtures thereof. In particular, the pH adjuster is selected from the group consisting of triethanolamine, sodium hydroxide, lactic acid, and citric acid.

[0095] Examples of suitable antioxidants include, but are not limited to, free radical scavengers or reducing agents such as acetylcysteine, ascorbic acid, ascorbyl palmitate, butylated hydroxytoluene, green tea extract, caffeic acid, cysteine, tocopherol, ubiquinone, propyl gallate, butylated hydroxytoluene (BHT), and mixtures thereof. In particular, the antioxidant is selected from the group consisting of ascorbyl palmitate, and tocopherol.

[0096] Examples of suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, propylparaben, methylparaben, sorbic acid, potassium sorbate, sodium benzoate, phenoxyethanol, triclosan, or mixtures thereof. In particular, the preservative is selected from the group consisting of potassium sorbate, sodium benzoate, and phenoxyethanol.

[0097] Examples of suitable viscosity agents include, but are not limited to, cellulose or its derivatives, such as hydroxypropylmethylcellulose, polyethylene glycol, microcrystalline cellulose, cetearyl alcohol, alginates, branched polysaccharides, fumed silica, xanthan gum, carbomer, and polyacrylates. In particular, the viscosity agent is selected from the group consisting of microcrystalline cellulose, cetearyl alcohol, cellulose, xanthan gum, and carbomer.

[0098] The composition also includes a vehicle. Examples of vehicles include, but are not limited to, water, propylene glycol, butylene glycol, ethanol, isopropanol, or silicone.

[0099] The topical compositions of the present invention can be formulated in several forms, including, but not limited to, solutions, aerosol and non-aerosol sprays, shaving creams, powders, mousses, lotions, gels, sticks, ointments, pastes, creams, shampoos, shower gels, body washes or facial cleansers.

[0100] The topical compositions of the present invention can be prepared according to methods well known in the art. Suitable excipients and / or carriers and their amounts can be easily determined by those skilled in the art depending on the type of formulation to be prepared.

[0101] In one embodiment of the second aspect of the present invention, the topical cosmetic composition is in the form of a patch.The patch can be adhesive or non-adhesive.In one embodiment of the second aspect of the present invention, optionally in combination with any of the above or below embodiments, the patch can be attached to skin and comprises a matrix comprising at least one polymer and one or more peptides defined according to the first aspect of the present invention or any of the above embodiments, or acceptable salt(s) thereof.

[0102] The peptides of the invention may also be adsorbed onto solid organic polymers or solid inorganic substrates, such as, for example, but not limited to, talc, bentonite, silica, starch, maltodextrin.

[0103] The composition comprising the peptide of the present invention can also be incorporated into fabrics, nonwovens, and medical devices that directly contact the skin, so that the peptide of the present invention is released by biodegradation of the fixing system to the fabric, nonwovens, and medical devices, or by friction with the body, body moisture, skin pH value, or body temperature.In addition, the fabrics and nonwovens can also be used to manufacture clothing that directly contacts the body.Illustrative non-limiting examples of fabrics, nonwovens, clothing, and medical devices are bandages, gauze, shirts, socks, stockings, girdles, gloves, diapers, sanitary napkins, bandages, bed covers, wet tissues, hydrogels, adhesive patches, non-adhesive patches, micro-electrical patches, and / or face masks.

[0104] In another embodiment, the cosmetic composition of the second aspect of the present invention is in an injectable form, either in an epidermal, dermal, and / or subcutaneous injectable form.In this embodiment, the composition comprises one or more macromolecules of the extracellular matrix, such as hyaluronic acid, collagen, and / or cells, and / or an injection vehicle, such as a preparation extracted from adipose tissue or comprising a cosmetically acceptable excipient or carrier as disclosed above.In a particular embodiment, the composition in an injectable form is a solution, gel, or hydrogel.

[0105] The cosmetic composition, preferably in injectable form as defined above, is also very suitable for mesotherapy. Mesotherapy is a non-surgical cosmetic treatment technique that involves the injection of an agent(s) (micronutrients, vitamins, mineral salts, etc.) into the epidermis, into the dermis, and / or subcutaneously. The composition is administered in the form of small droplets into the epidermis, the dermo-epidermal junction, and / or into the dermis. To that end, the formulation of the present disclosure can be injected using a needle with a diameter of about 0.26 to about 0.4 mm and a length of about 4 to about 14 mm. Alternatively, the needle can be 21 to 32 G and have a length of about 4 mm to about 70 mm. In particular, the needle is a single-use needle. The needle can be combined with a syringe, a catheter, and / or a pistol (e.g., a hydropneumatic-compression pistol). The formulation can be administered to the subject once or over several sessions spaced apart by days or weeks. For example, the subject can be administered the formulation every 1, 2, 3, 4, 5, 6, 7 days, or every 1, 2, 3, or 4 weeks. Administration can be monthly or bimonthly. Furthermore, the formulation can be administered every 3, 6, 9, or 12 months.

[0106] Thus, the cosmetic composition of the present invention may be suitable for intradermal injection, or for mesotherapy, by using a syringe, one or more microneedles, an implant, or a biodegradable reservoir.

[0107] The term "biodegradable reservoir" refers to a device that contains molecules that are capable of degrading over an extended period of time, often weeks to months or years, after being introduced into the skin.

[0108] In a particular embodiment, the composition suitable for intradermal or mesotherapy is as defined in any of the embodiments defining a cosmetic composition in injectable form.

[0109] The present invention includes the use of a cosmetically effective amount of a peptide as defined in the first aspect of the invention or a composition as defined in the second aspect of the invention to improve the physical appearance of a mammal having hernia or accumulation of subcutaneous fat in the fibrous connective tissue beneath the skin. This aspect may also be formulated as a cosmetic method for improving the physical appearance of a mammal having hernia or accumulation of subcutaneous fat in the fibrous connective tissue beneath the skin comprising administering a cosmetically effective amount of a peptide as defined in the first aspect of the invention or a composition as defined in the second aspect of the invention together with a cosmetic excipient or carrier.

[0110] Subcutaneous fat is found just under the skin, whereas visceral fat is found within the abdominal cavity. Subcutaneous fat can be measured using a body fat caliper, which provides a rough estimate of total body fat. This fat aids in the homeostatic process by forming an insulating layer to slow heat loss.

[0111] Fibrous connective tissue is a fraction that contains fibroblasts and extracellular matrix components from subcutaneous tissue (or connective tissue). Whole connective tissue also contains adipocytes and macrophages. Subcutaneous tissue is mainly used to store fat. Therefore, in a particular embodiment, the cosmetic use is for mammals with cellulite.

[0112] In particular, the cosmetic effect of the peptides, compositions, kits and devices of the present invention is derived from the lipolytic effect they provide. Thus, topical or transdermal administration of the peptides of the present invention results in the reduction of subcutaneous fat that has leaked or accumulated in fibrous connective tissue, or, equivalently, reduces cellulite, which is often topographically manifested as skin dimples and nodules on the pelvic region (particularly the buttocks), lower legs and abdomen of women.

[0113] The cosmetic use of the peptide and cosmetic composition according to the present invention is intended for application to mammals, particularly humans, who are healthy subjects without necessarily having any disease. That is, the subject may not be obese, overweight, or suffer from fatty liver. The cosmetic use is only for aesthetic purposes, aimed at improving physical appearance, and is not intended for the treatment of any disease. Generally speaking, in cosmetic use, the peptide only needs to reach the accumulated or stored fat at subcutaneous level, so the cosmetically effective amount is different from the therapeutically effective amount.

[0114] In certain embodiments, the use of the peptides and cosmetic compositions of the present invention in cosmetics (or cosmetic use) is not a surgical cosmetic use, a use in a surgical cosmetic method, or a use that includes a surgical step.In another embodiment, the use of the peptides or cosmetic compositions of the present invention in improving the physical appearance of a mammalian subject having a prolapsed or accumulated subcutaneous fat in the fibrous connective tissue under the skin is not a surgical use, a use in a surgical method, or a use that includes a surgical step.In another embodiment, the cosmetic method of the present invention is a non-surgical cosmetic method, or a method that does not include a surgical step.

[0115] In a third aspect, the present invention provides a pharmaceutical composition comprising one or more peptides as defined in the first aspect of the invention and any of the above embodiments.

[0116] The term "pharmacologically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must be "acceptable" in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, and examples include preservatives, flocculants, humectants, emollients, and antioxidants.

[0117] As used herein, the term "therapeutically effective amount" means an amount of an active agent that is sufficient to deliver the desired effect (either treatment or prevention of a disease) yet low enough, within the bounds of medical judgment, to avoid significant side effects.

[0118] In one embodiment of the third aspect of the present invention, the pharmaceutical composition is an oral pharmaceutical composition. Illustrative non-limiting examples of oral pharmaceutical compositions include tablets, capsules, granules, or pellets.

[0119] Suitable excipients and / or carriers, as well as their amounts, can be readily determined by one skilled in the art depending on the type of formulation being prepared.

[0120] Due to its role as lipolytic agent, the peptide of the present invention is also suitable for treating diseases caused by lipid accumulation in internal organs such as liver, heart or kidney.Exemplary non-limiting examples of lipid accumulation diseases include fatty liver, diabetes or cardiovascular disease.Therefore, the peptide as defined in the first aspect of the present invention and any of the above embodiments for use in therapy, particularly for use in the treatment and / or prevention of diseases caused by or related to lipid accumulation in internal organs, is also part of the present invention.

[0121] This aspect of the invention may also be described as the use of a peptide as defined in the first aspect of the invention for the manufacture of a medicament for the treatment and / or prevention of a disease selected from the group consisting of overweight, obesity, fatty liver, diabetes and cardiovascular disease in a mammal, such as a human.

[0122] The present invention also relates to a method for the treatment and / or prevention of a disease selected from the group consisting of overweight, obesity, fatty liver, diabetes and cardiovascular disease in a mammal, such as a human, comprising administering a therapeutically effective amount of a peptide as defined in the first aspect of the invention, together with a pharma- ceutically acceptable excipient and / or carrier.

[0123] In an embodiment of the fifth aspect of the invention, the use of a peptide as defined in the first aspect of the invention as a lipolytic agent is not a therapeutic use or a use in a therapeutic treatment. In another embodiment of the fifth aspect of the invention, the use of a peptide as defined in the first aspect of the invention as a lipolytic agent is not a treatment by, or in, a surgical treatment or a use involving a surgical step.

[0124] Throughout the description and claims, the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components, or steps. Furthermore, the term "comprise" encompasses the case of "consisting of". Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of the detailed description or may be learned by the practice of the present invention. The following examples and drawings are provided by way of illustration and are not intended to limit the present invention. Reference signs placed in parentheses in connection with the drawings and in the claims are intended only to enhance the completeness of the claims and shall not be construed as limiting the scope of the claims. Furthermore, the present invention includes all possible combinations of specific preferred embodiments described herein.

[0125] Working Example I. Synthesis of the Peptides of the Invention Synthesis method A: Fmoc solid phase synthesis route to EDL3D: TWDPEGVIFY (all D amino acids) 1. Fmoc-D-Tyr(tbu)-resin was swollen in DCM for 30 min. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.26 g of Fmoc-D-Phe-OH was coupled and allowed to react for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. 0.24 g of Fmoc-allo-D-Ile-OH, 0.23 g of Fmoc-D-Val-OH, 0.20 g of Fmoc-D-Gly-OH, 0.29 g of Fmoc-D-Glu-OH, 0.23 g of Fmoc-D-Pro-OH, 0.28 g of Fmoc-D-Asp-OH, and 0.36 g of Fmoc-D-Trp-OH were coupled in this order, and each reaction was carried out for 30 minutes, and then the reaction proceeded to step 2. 6. Couple the last amino acid, 0.27 g of Fmoc-D-Thr(tbu)-OH, react for 30 min, if test passed, wash 3 times with DMF; DBLK deprotection step for 15 min. 7. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0126] Synthesis method B: Fmoc solid phase synthesis route of EDL3D-A: Ac-TWDPEGVIFY (all D amino acids) 1. Fmoc-D-Tyr(tbu)-resin was swollen in DCM for 30 min. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.26 g of Fmoc-D-Phe-OH was coupled and allowed to react for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-allo-D-Ile-OH 0.24 g, Fmoc-D-Val-OH 0.23 g, Fmoc-D-Gly-OH 0.20 g, Fmoc-D-Glu-OH 0.29 g, Fmoc-D-Pro-OH 0.23 g, Fmoc-D-Asp-OH 0.28 g, and Fmoc-D-Trp-OH 0.36 g were coupled in sequence, and each reaction was carried out for 30 minutes, then proceeded to steps 4 and 2. 6. The final AA, 0.27 g of Fmoc-D-Thr(tbu)-OH, was coupled and reacted for 30 min, and steps 4 and 2 were repeated. 7. AC reaction was carried out with a certain ratio of acetic anhydride and 85% azabenzene, left for 30 minutes, and step 4 was repeated. 8. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0127] Synthesis method C: Fmoc solid phase synthesis route of EDL3D-NH2:TWDPEGVIFY-NH3 (all D amino acids) 1. Fmoc-Rink amide MBHA resin was swollen in DCM for 30 minutes. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.26 g of Fmoc-D-Tyr(tbu)-OH was coupled and reacted for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-D-Phe-OH 0.26 g, Fmoc-allo-D-Ile-OH 0.24 g, Fmoc-D-Val-OH 0.23 g, Fmoc-D-Gly-OH 0.20 g, Fmoc-D-Glu-OH 0.29 g, Fmoc-D-Pro-OH 0.23 g, Fmoc-D-Asp-OH 0.28 g, and Fmoc-D-Trp-OH 0.36 g were coupled in sequence, and each reaction was carried out for 30 minutes, then proceeded to steps 4 and 2. 6. The final AA, 0.27 g of Fmoc-D-Thr(tbu)-OH, was coupled and reacted for 30 min, followed by repeating step 4, washing with DMF three times, and DBLK deprotection treatment for 15 min. 7. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0128] Synthesis method D: Fmoc solid phase synthesis route of EDL3D-NH2 / Ac: Ac-TWDPEGVIFY-NH2 (all D amino acids) 1. Fmoc-Rink amide MBHA resin was swollen in DCM for 30 minutes. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.26 g of Fmoc-D-Tyr(tbu)-OH was coupled and reacted for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-D-Phe-OH 0.26 g, Fmoc-allo-D-Ile-OH 0.24 g, Fmoc-D-Val-OH 0.23 g, Fmoc-D-Gly-OH 0.20 g, Fmoc-D-Glu-OH 0.29 g, Fmoc-D-Pro-OH 0.23 g, Fmoc-D-Asp-OH 0.28 g, and Fmoc-D-Trp-OH 0.36 g were coupled in sequence, and each reaction was carried out for 30 minutes, then proceeded to steps 4 and 2. 6. The final AA, 0.27 g of Fmoc-D-Thr(tbu)-OH, was coupled and reacted for 30 min, and steps 4 and 2 were repeated. 7. AC reaction was carried out with a certain ratio of acetic anhydride and 85% azabenzene, left for 30 minutes, and step 4 was repeated. 8. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0129] Synthesis Method E: Fmoc Solid Phase Synthesis Route of GP3DM-25: Ac-NDLEGLY (All D Amino Acids) 1. Fmoc-D-Tyr(tbu)-Wang resin was swollen in DCM for 30 minutes. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.3 g of Fmoc-D-Leu-OH was coupled and reacted for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-Gly-OH 0.26 g, Fmoc-D-Glu(Otbu)-OH 0.38 g, Fmoc-D-Leu-OH 0.3 g, Fmoc-D-Asp(Otbu)-OH 0.37 g, and Fmoc-D-Asn(Trt)-OH 0.53 g were coupled in sequence, and each reaction was carried out for 30 minutes, and then proceeded to steps 4 and 2. 6. The final AA, 2.25 pyridine:4.5 acetic anhydride in 1 ml of CHCO for 30 min, was then repeated with step 4, washed 3 times with DMF, and the DBLK deprotection step was carried out for 15 min. 7. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0130] Synthetic Method F: Fmoc Solid Phase Synthesis Route of GP3DM-26: EtCONH-NDLEGLY (All D Amino Acids) 1. Fmoc-D-Tyr(tbu)-Wang resin was swollen in DCM for 30 minutes. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.3 g of Fmoc-D-Leu-OH was coupled and reacted for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-Gly-OH 0.26 g, Fmoc-D-Glu(Otbu)-OH 0.38 g, Fmoc-D-Leu-OH 0.3 g, Fmoc-D-Asp(Otbu)-OH 0.37 g, and Fmoc-D-Asn(Trt)-OH 0.53 g were coupled in sequence, and each reaction was carried out for 30 minutes, and then proceeded to steps 4 and 2. 6. The final AA, 0.066 g CH3CH2CO, was coupled and reacted for 30 min, step 4 was repeated, washed 3 times with DMF, and DBLK deprotection treatment was performed for 15 min. 7. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0131] Synthesis method G: Fmoc solid phase synthesis route of GP3DM-27: Ac-NDPEGLY-NH2 (all D-amino acids) 1. Fmoc-Rink amide MBHA resin was swollen in DCM for 30 minutes. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.41 g of Fmoc-D-Tyr(tBu)-OH was coupled and reacted for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-D-Leu-OH 0.3 g, Fmoc-Gly-OH 0.26 g, Fmoc-D-Glu(Otbu)-OH 0.38 g, Fmoc-D-Pro-OH 0.3 g, Fmoc-D-Asp(Otbu)-OH 0.37 g, and Fmoc-D-Asn(Trt)-OH 0.53 g were coupled in sequence, and each reaction was carried out for 30 minutes, and then proceeded to steps 4 and 2. 6. The final AA, 2.25 pyridine:4.5 acetic anhydride in 1 ml of CHCO for 30 min, was then repeated with step 4, washed 3 times with DMF, and the DBLK deprotection step was carried out for 15 min. 7. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0132] Synthesis Method H: Fmoc Solid Phase Synthesis Route of GP3DM-28: CH3(CH2)14CONH-NDLEGLY (All D-Amino Acids) 1. Fmoc-D-Tyr(tBu)-Wang resin was swollen in DCM for 30 minutes. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.3 g of Fmoc-D-Leu-OH was coupled and reacted for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-Gly-OH 0.26 g, Fmoc-D-Glu(Otbu)-OH 0.38 g, Fmoc-D-Leu-OH 0.3 g, Fmoc-D-Asp(Otbu)-OH 0.37 g, and Fmoc-D-Asn(Trt)-OH 0.53 g were coupled in sequence, and each reaction was carried out for 30 minutes, and then proceeded to steps 4 and 2. 6. The final AA, 0.23 g of CH3(CH2)14CO, was coupled and reacted for 30 min, followed by repeating step 4, washing with DMF three times, and DBLK deprotection treatment for 15 min. 7. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0133] Synthetic Method I: Fmoc Solid Phase Synthesis Route of GP3DM-29: Ac-NDLEGLY-NH2 (All D Amino Acids) 1. Fmoc-Rink amide MBHA resin was swollen in DCM for 30 minutes. 2. Washed 3 times with DMF and DBLK deprotection treatment for 15 minutes; washed 6 times with DMF. 3. 0.41 g of Fmoc-D-Tyr(tBu)-OH was coupled and reacted for 30 minutes. 4. If the test passed (the solution was bright yellow and the resin was clear); repeat step 2. 5. Fmoc-D-Leu-OH 0.3 g, Fmoc-Gly-OH 0.26 g, Fmoc-D-Glu(Otbu)-OH 0.38 g, Fmoc-D-Leu-OH 0.3 g, Fmoc-D-Asp(Otbu)-OH 0.37 g, and Fmoc-D-Asn(Trt)-OH 0.53 g were coupled in sequence, and each reaction was carried out for 30 minutes, and then proceeded to steps 4 and 2. 6. The final AA, 2.25 pyridine:4.5 acetic anhydride in 1 ml of CHCO for 30 min, was then repeated with step 4, washed 3 times with DMF, and the DBLK deprotection step was carried out for 15 min. 7. The product was washed three times each with DMF, DCM, and MeOH, respectively, and then purified and lyophilized after cleavage.

[0134] Purification method: HPLC: 1: MS detection shows the product is correct. 2: Dissolve the peptide sample (0.5 mg) and use HPLC (10-100% gradient) to obtain the actual peak time. [Table 1] 3: Prepare the gradient accordingly (ACN:H 2 O=1:7 Gradient=12~22%) [Table 2] 4. Purity detection: Collect the correct sample according to the detection. [Table 3] 5: Evaporate the collected product on a rotary evaporator 6: Freeze-dry at -50°C. 7: Retest using HPLC to check the final purity of the dried product. [Table 4]

[0135] MS: 1: Take 0.1 mg of the crude product and dissolve it in ACN:H2O=2:1 (it will look clear). 2: Clean the product using a B-2060 ultrasonic cleaner (30 seconds). 3: Centrifuge using the RJ-TGL-16B centrifuge (1 minute) 4. Inject 0.5ul into the LCMS-2010EV MS detector and examine the peaks. Peptide characterization data is shown below in Tables 5A and 5B.

[0136] II. Lipolytic activity Lipolytic activity was measured as glycerol (μM) release upon addition of either caffeine or peptides (SEQ ID NOs: 2-38 and 53) to cultures of differentiated 3T3-L1 cell line mouse adipocytes (reference JCRB9014-A) (Tebu-Bio, Barcelona, ​​Spain). Briefly, mouse adipocytes (3T3-L1 cells) were cultured in 48-well plates as previously described (Saez-Lopez et al., 2020). Adipocytes were differentiated using cell culture reagents purchased from Tebu-Bio according to the manufacturer's instructions. On day 10 of differentiation, cells were treated twice with vehicle (DMSO), caffeine (100 μg / ml), and each of the peptides at the doses specified in Table 6a below. Supernatants were collected at the end of the experiment (after 12 hours) and glycerol content was measured using a glycerol assay kit (Sigma) according to the manufacturer's instructions.

[0137] The same protocol was repeated again for some of the peptides at a concentration of 100 μg / mL using human adipocytes (Tebu-Bio) instead of mouse adipocytes. The results are summarized in Table 6b below. Lipolytic activity was measured as glycerol (μM) using a lipolysis assay kit (LIP-1-NC) (Tebu-bio) according to the manufacturer's instructions.

[0138] The results are summarized in Tables 6a and 6b below. As can be derived, the peptides of the present invention (SEQ ID NOs: 3-38, 55-71, 80-87) were found to be significantly more efficient than caffeine after 12 hours. This shows an improvement in efficiency that was found over an extended period of time, at least in the 12 hour test, even when low doses were used.

[0139] On the other hand, Table 6b also confirms the improved lipolytic effect provided by the peptides of the invention when compared to caffeine or Hexa-39.

[0140] III. Time course of lipolytic activity Lipolytic activity was measured as glycerol (μM) release in differentiated human subcutaneous adipocytes treated for 120 and 240 min with 10 μg / ml caffeine; or, for comparison, 10 μg / ml of peptide of SEQ ID NO: 2; or 10 μg / ml of the peptide of the invention of SEQ ID NO: 3. Supernatants were collected at the end of the experiment and glycerol content was measured using a Lipolysis Assay Kit (LIP-1-NC) (Tebu-bio) according to the manufacturer's instructions.

[0141] The results are summarized in Table 7 below. As can be derived from the table below, the peptides of the present invention provided significant amounts of glycerol at 120 minutes, indicating a lipolytic effect. In contrast, neither caffeine nor the comparative peptides provided any significant activity at that time point at the same dose.

[0142] On the other hand, Table 7 again highlights the improved efficiency of inducing lipolysis when using peptides of the invention, even after a very short time after administration: in this case, peptide SEQ ID NO:3 was found to be more than 24 times more efficient at 120 min and more than 5 times more efficient at 240 min compared to caffeine or SEQ ID NO:2.

[0143] In conclusion, the peptides of the present invention not only provide lipolytic activity more efficiently, but also (1) induce the onset of lipolytic activity significantly earlier, and (2) sustain the lipolytic effect for a longer period of time. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0144] Terms For reasons of completeness, the various aspects of the invention are set out in the following numbered clauses:

[0145] Clause 1. (a) having a sequence of 5 to 9 amino acids in length, each amino acid being either an L-amino acid or a D-amino acid, the peptide corresponding to the sequence of SEQ ID NO: 54, or an acceptable salt thereof: (T) a (X 1 ) b D(X 2 ) g EG(X 3 ) c (X 4 ) d (X 5 ) e (Y) f During the ceremony: X 1 represents W, N, Q or K; X 2 represents P, N, a basic amino acid, or a hydrophobic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; X 5 represents F or P, the subscripts "a", "b", "c", "d", "e", "f" and "g" are integers independently selected from 0 and 1; provided that two, three, four, five or six of the subscripts "a", "b", "c", "d", "e", "f" and "g" represent 1 and the remaining subscripts represent 0; or, (b) a lipolytic peptide selected from the group consisting of SEQ ID NOs: 39-46 and any salts thereof; The N-terminus of the lipolytic peptide is -NR 1 R 2 Corresponding to R 1 and R 2 -H, -C(O)R 3 , triglycerides and (C 1 ~C 20 ) alkyl; The C-terminus of the lipolytic peptide is -COOR 4 or -C(O)NR 5 R 6 Corresponding to; R 3 ~R 6 is -H and (C 1 ~C 20 ) alkyl, independently selected from the group consisting of:

[0146] Clause 2. (a) A peptide having a sequence of 5 to 9 amino acids in length, each amino acid being an L-amino acid or a D-amino acid, the peptide corresponding to the sequence of SEQ ID NO: 1 or an acceptable salt thereof: (T) a (X 1 ) b D(X 2 )EG(X 3 ) c (X 4 ) d (F) e (Y) f During the ceremony: X 1 represents W, N, Q or K; X 2 represents P, N, or a basic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; the subscripts "a", "b", "c", "d", "e", and "f" are integers independently selected from 0 and 1, with the proviso that 1, 2, 3, 4, or 5 of the subscripts "a", "b", "c", "d", "e", and "f" represent 1 and the remaining subscripts represent 0; or, (b) a lipolytic peptide selected from the group consisting of SEQ ID NOs: 39-46 and any acceptable salts thereof; The N-terminus of the lipolytic peptide is -NR 1 R 2 Corresponding to R 1 and R 2 -H, -C(O)R 3 , triglycerides and (C 1 ~C 20 ) alkyl; The C-terminus of the lipolytic peptide is -COOR 4 and -C(O)NR 5 R 6 Corresponding to; R 3 ~R 6 is -H and (C 1 ~C 20 ) alkyl, independently selected from the group consisting of:

[0147] Clause 3. (a) A peptide having a sequence of 5 to 9 amino acids in length, each amino acid being an L-amino acid or a D-amino acid, the peptide corresponding to the sequence of SEQ ID NO: 1 or an acceptable salt thereof: (T) a (X 1 ) b D(X 2 )EG(X 3 ) c (X 4 ) d (F) e (Y) f During the ceremony: X 1 represents W, N, or Q; X 2represents P, N, or a basic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; the subscripts "a", "b", "c", "d", "e", and "f" are integers independently selected from 0 and 1, with the proviso that 1, 2, 3, 4, or 5 of the subscripts "a", "b", "c", "d", "e", and "f" represent 1 and the remaining subscripts represent 0; or alternatively (b) a lipolytic peptide selected from the group consisting of SEQ ID NOs: 39-46 and any acceptable salts thereof; The N-terminus of the lipolytic peptide is -NR 1 R 2 Corresponding to R 1 and R 2 -H, -C(O)R 3 , triglycerides and (C 1 ~C 20 ) alkyl; The C-terminus of the lipolytic peptide is -COOR 4 and -C(O)NR 5 R 6 Corresponding to; R 3 ~R 6 is -H and (C 1 ~C 20 ) alkyl, independently selected from the group consisting of:

[0148] Clause 4. (a) A peptide having a sequence of 5 to 9 amino acids in length, each amino acid being an L-amino acid or a D-amino acid, the peptide corresponding to the sequence of SEQ ID NO: 1 or an acceptable salt thereof: (T) a (X 1 ) b D(X 2 )EG(X 3 ) c (X 4 ) d (F) e (Y)f During the ceremony: X 1 represents W or N; X 2 represents P, N, or a basic amino acid; X 3 and X 4 are the same or different and represent A, V, L or I; the subscripts "a", "b", "c", "d", "e", and "f" are integers independently selected from 0 and 1, with the proviso that 1, 2, 3, 4, or 5 of the subscripts "a", "b", "c", "d", "e", and "f" represent 1 and the remaining subscripts represent 0; or alternatively (b) a lipolytic peptide selected from the group consisting of SEQ ID NOs: 39-46 and any acceptable salts thereof; The N-terminus of the lipolytic peptide is -NR 1 R 2 Corresponding to R 1 and R 2 -H, -C(O)R 3 , triglycerides and (C 1 ~C 20 ) alkyl; The C-terminus of the lipolytic peptide is -COOR 4 and -C(O)NR 5 R 6 Corresponding to; R 3 ~R 6 is -H and (C 1 ~C 20 ) alkyl, independently selected from the group consisting of:

[0149] Clause 5. A lipolytic peptide according to any one of the preceding clauses, which is a peptide selected from SEQ ID NOs: 39 to 42, in which two or more of the amino acids are D-amino acids, in particular all amino acids are D-amino acids, or alternatively selected from SEQ ID NOs: 43 to 46 and any acceptable salts thereof, in which one or more of the amino acids forming the peptide are D-amino acids, in particular all of the amino acids forming the peptide are D-amino acids.

[0150] Article 6.X 1 represents W or N, preferably W; in particular X 1 is a D-amino acid DW or DN.

[0151] Clause 7. A peptide of sequence SEQ ID NO: 1 or a salt thereof as defined above, 2 represents P or N; X 2 The lipolytic peptide according to any one of the preceding clauses, wherein represents a D-amino acid selected from DP and DN.

[0152] Clause 8. A peptide having the sequence of SEQ ID NO: 1 or a salt thereof, as defined above, wherein X 3 and X 4 are the same or different and represent V, L or I; in particular, X 3 and X 4 The lipolytic peptide according to any one of the preceding clauses, wherein are the same or different and represent D-amino acids selected from DV, DL and DI.

[0153] Clause 9. The lipolytic peptide according to any of the preceding clauses, selected from the group consisting of sequences SEQ ID NOs: 47 to 49 and any salts thereof: SEQ ID NO:47 (T) a (X 1 ) b DPEGV(X 4 ) d (F) e (Y) f, where "a", "b", "d", "e", and "f" are as defined in clause 1, and X 1 represents W or N, and X 4 represents I or L; SEQ ID NO:48 (T) a (X 1 ) b DPEGX 3 (F) e (Y) f , where "a", "b", "e", and "f" are as defined in clause 1, and X 1 represents W or N, and X 3 represents I or L; SEQ ID NO:49 (T) a (W) b DNEG(X 3 )(F) e (Y) f , where "a", "b", "e", and "f" are as defined in clause 1, and X 3 represents I or L, in particular L.

[0154] Clause 10. The lipolytic peptide according to any of the preceding clauses, which is a peptide of sequence SEQ ID NO: 73 and any salt thereof. SEQ ID NO:73 NDPEG(L) c Y, where "c" is as defined above in SEQ ID NO:1 and clause 1.

[0155] Clause 11. The lipolytic peptide according to any one of the preceding clauses, which is a peptide of sequence SEQ ID NO: 1, 43-48 or an acceptable salt thereof, wherein one or more of the amino acids forming the peptide are D-amino acid(s).

[0156] Clause 12. The lipolytic peptide according to any one of the preceding clauses, which is a peptide of sequence SEQ ID NO: 49 or 73 or an acceptable salt thereof, wherein one or more of the amino acids forming the peptide are D-amino acid(s).

[0157] Clause 13. The peptide of any one of clauses 11 or 12, wherein all of the amino acids forming the peptide are D-amino acids.

[0158] Clause 14. A peptide having a sequence of 5 to 9 amino acids in length, which corresponds to the sequence of SEQ ID NO: 54, wherein X 1 represents N, and especially X 1 A lipolytic peptide according to clause 1, wherein:

[0159] Clause 15. A peptide having a sequence of 5 to 9 amino acids in length, which corresponds to the sequence of SEQ ID NO: 54, wherein X 2 is P, L, V or A, in particular stands for DP, DL, DV or DA.

[0160] Clause 16. A peptide having a sequence length of 5 to 9 amino acids, which corresponds to the sequence of SEQ ID NO: 54, wherein X 3 and X 4 are the same or different and represent L, V, or A; in particular X 3 and X 4 is the same or different and represents DL, DV or DA.

[0161] Clause 17. A peptide having a sequence of 5 to 9 amino acids in length, which corresponds to the sequence of SEQ ID NO: 54, wherein X 5 represents F or P, in particular DF ​​or DP.

[0162] Clause 18. The lipolytic peptide according to any one of clauses 1, 14 to 17, which is a peptide of sequence SEQ ID NO: 54, 72 to 75 or a salt thereof: SEQ ID NO: 72 ND(X 2 ) g EG(X 3 ) c (X 5 ) eY, where "g", "c" and "e" are as defined above for SEQ ID NO:54 and in clause 1; 2 represents V, A, L, or P, and X 3 stands for L, V, or A, and X 5 represents P or F. SEQ ID NO:73 NDPEG(L) c Y, where "c" is as defined above in SEQ ID NO:54 or SEQ ID NO:1 and clause 1. SEQ ID NO: 74 ND(X 2 ) g (X 3 ) c (X 5 ) e Y, where "c", "e" and "g" are as defined above for SEQ ID NO:54 and in clause 1; 2 represents V, A or L, and X 3 represents L, V, A, and X 5 represents F or P. Sequence number 75ND(X 2 ) g EGLY, where "g" is as defined above for SEQ ID NO:54 and clause 1; and X 2 is P or L.

[0163] Clause 19. The lipolytic peptide according to any one of clauses 1, 14 to 18, which is a peptide of sequence SEQ ID NO: 54, 72, 74 or 75 or a salt thereof.

[0164] Clause 20. The lipolytic peptide according to any one of clauses 1, 14 to 18, which is a peptide of sequence SEQ ID NO: 54, 72 to 75 or an acceptable salt thereof, wherein one or more of the amino acids forming the peptide is a D-amino acid(s).

[0165] Clause 21. The lipolytic peptide according to any one of clauses 1, 14 to 19, which is a peptide of sequence SEQ ID NO: 54, 72, 74 or 75 or an acceptable salt thereof, wherein one or more of the amino acids forming the peptide is a D-amino acid(s).

[0166] Clause 22. The lipolytic peptide according to any one of clauses 20 or 21, wherein all of the amino acids forming the peptide are D-amino acids.

[0167] Clause 23. The N-terminus is -NH 2 or -NHC(O)R 3 and R 3 However, (C 1 ~C 20 ) alkyl. The peptide or salt thereof according to any one of the preceding clauses.

[0168] Clause 24. The N-terminus is -NHC(O)R 3 and R 3 However, (C 1 ~C 15 ) alkyl. The peptide or salt thereof according to any one of the preceding clauses.

[0169] Clause 25. The N-terminus is -NHC(O)R 3 and R 3 However, (C 1 ~C 10 ) alkyl. The peptide or salt thereof according to any one of the preceding clauses.

[0170] Clause 26. The C-terminus is -COOH, -C(O)NH 2 , -C(O)NHR 6 where R 6 However, (C 1 ~C 20 ) alkyl. The peptide or salt thereof according to any one of the preceding clauses.

[0171] Clause 27. The peptide or salt thereof according to any one of the preceding clauses, selected from the group consisting of SEQ ID NOs: 3 to 38, 55 to 71, 80 to 87 and acceptable salts thereof.

[0172] Clause 28. The peptide or salt thereof according to any one of the preceding clauses, selected from the group consisting of SEQ ID NOs: 3-38, 61, 66, 69, 80-87 and acceptable salts thereof.

[0173] Clause 29. The peptide according to any one of the preceding clauses, or a salt thereof, selected from the group consisting of SEQ ID NOs: 55-60, 62-65, 67, 68, 70 and 71 and acceptable salts thereof.

[0174] Clause 30. A cosmetic composition comprising a cosmetically effective amount of a peptide or salt thereof as defined in any one of the preceding clauses together with one or more cosmetically acceptable carriers or excipients.

[0175] Clause 31. The cosmetic composition of clause 30, further comprising one or more of an additional lipolytic agent, a vasoprotectant or vasodilator, retinol, a sunscreen, a vitamin, an alpha-hydroxy acid, a surfactant, a dye, a fragrance, and a pigment.

[0176] Clause 32. A cosmetic composition according to clause 30 or clause 31, which is a topical or injectable cosmetic composition.

[0177] Clause 33. The cosmetic composition according to any of clauses 30 to 32, which is a topical composition selected from solutions, aerosol and non-aerosol sprays, shaving creams, powders, mousses, lotions, gels, sticks, ointments, pastes, creams, shampoos, shower gels, body washes or facial cleansers.

[0178] Clause 34. The cosmetic composition according to clause 30 or 31, which is in the form of a patch.

[0179] Clause 35. An injection device, such as an intradermal injection device, pre-loaded with a peptide as defined in any of the preceding clauses 1 to 29 or a cosmetic composition as defined in the preceding clauses 30 or 31.

[0180] Clause 36. A pharmaceutical composition comprising a therapeutically effective amount of a peptide as defined in any of clauses 1 to 29 and one or more therapeutically acceptable excipients or carriers.

[0181] Clause 37. A peptide as defined in any one of the preceding clauses 1 to 29, or a cosmetic composition as defined in clause 30 or 31, or a pharmaceutical composition as defined in clause 36; and a device selected from the group consisting of an intradermal injection device, an implant, or a biodegradable container.

[0182] Clause 38. Use of a peptide as defined in any of the preceding clauses 1 to 29 as a lipid lowering agent, in particular a lipolytic agent.

[0183] Clause 39. Use of a peptide as defined in clause 38 for therapeutic use, which use is not a surgical procedure or which does not involve the step of a surgical procedure.

[0184] Clause 40. Use of a peptide as defined in any one of the preceding clauses 1 to 29, or a cosmetic composition as defined in any one of the preceding clauses 30 to 34, or an injection device as defined in clause 35, or a kit as defined in clause 37 in a cosmetic product.

[0185] Clause 41. Use according to clause 40, which is not a surgical cosmetic use or a use in a surgical cosmetic method or a use which includes a surgical treatment step.

[0186] Clause 42. A peptide as defined in any one of the preceding clauses 1 to 29, or a pharmaceutical composition as defined in clause 36, or a kit as defined in clause 37, for use in therapy.

[0187] Clause 43. Use of a cosmetically effective amount of a peptide as defined in any one of clauses 1 to 29 above or a cosmetic composition as defined in any one of clauses 30 to 34, or an injection device as defined in clause 35, or a kit of parts as defined in clause 37, in improving the physical appearance of a mammal having herniated or accumulated subcutaneous fat in the fibrous connective tissue beneath the skin.

[0188] Clause 44. Use according to clause 43, which is not a surgical use or a use in a surgical method or a use including a step of a surgical procedure.

[0189] Clause 45. A peptide as defined in any one of the preceding clauses 1 to 29, or a pharmaceutical composition as defined in clause 36, or a kit of parts as defined in clause 37, for use in the treatment of lipid accumulation in an internal organ. Citation List Non-patent literature:

[0190] - Saez-Lopez C. et al., “Sex hormone-binding globulin overexpression protects against high-fat diet-induced obesity in transgenic male mice”, J Nutr Biochem., 2020, 85:108480. doi:10.1016 / j.jnutbio.2020.108480

Claims

1. A lipolytic peptide, (a) having a sequence of 5 to 9 amino acids in length, each amino acid being either an L-amino acid or a D-amino acid, the peptide corresponding to the sequence of SEQ ID NO: 54 or an acceptable salt thereof: (T) ａ (X １ ) ｂ D(X ２ ) ｇ EG(X ３ ) ｃ (X ４ ) ｄ (X ５ ) ｅ (Y) ｆ During the ceremony: X １ represents W, N, Q or K; X ２ represents P, N, a basic amino acid or a hydrophobic amino acid; X ３ and X ４ are the same or different and represent A, V, L or I; X ５ represents F or P, the subscripts "a", "b", "c", "d", "e", "f", and "g" are integers independently selected from 0 and 1; provided that two, three, four, five, or six of the subscripts "a", "b", "c", "d", "e", "f", and "g" represent 1, and the remaining subscripts represent 0; or alternatively, (b) selected from the group consisting of SEQ ID NOs: 39-46 and any salt thereof; A lipolytic peptide; The N-terminus of the lipolytic peptide is -NR １ R ２ corresponds to R １ and R ２ is -H, -C(O)R ３ , triglycerides and (C １ ~C ２０ ) alkyl; The C-terminus of the lipolytic peptide is -COOR ４ or -C(O)NR ５ R ６ Corresponding to; R ３ ~R ６ is -H and (C １ ~C ２０ ) alkyl, Lipolytic peptides.

2. 2. The lipolytic peptide according to claim 1, wherein the peptide having a sequence of 5 to 9 amino acids in length corresponds to the sequence of SEQ ID NO: 1 or a salt thereof: (T) ａ (X １ ) ｂ D(X ２ )EG(X ３ ) ｃ (X ４ ) ｄ (F) ｅ (Y) ｆ During the ceremony: X １ represents W, N, Q or K; X ２ represents a P, N, or basic amino acid; X ３ and X ４ are the same or different and represent A, V, L or I; The subscripts "a", "b", "c", "d", "e", and "f" are integers independently selected from 0 and 1, provided that 1, 2, 3, 4, or 5 of the subscripts "a", "b", "c", "d", "e", and "f" represent 1 and the remaining subscripts represent 0.

3. A peptide of sequence SEQ ID NO: 1, having the following characteristics: -X １ represents W or N, and in particular X １ represents D-W or D-N; -X ２ represents P or N; in particular X ２ represents DP or DN; -X ３ and X ４ are the same or different and represent V, L or I; in particular X ３ and X ４ are the same or different and represent DV, DL or DI The lipolytic peptide of claim 2, having one or more of the following:

4. 2. The lipolytic peptide according to claim 1, which is a peptide of sequence SEQ ID NO: 1, 43-49 or 73 or a salt thereof, wherein one or more of the amino acids forming said peptide are D-amino acid(s); in particular, all of the amino acids forming said peptide are D-amino acids.

5. said peptide having a sequence of 5 to 9 amino acids in length corresponding to the sequence of SEQ ID NO: 54 and having the following characteristics: -X １ represents N, and in particular X １ represents D-N; -X ２ represents P, L, V, or A, in particular DP, DL, DV, or DA; -X ３ and X ４ are the same or different and represent L, V or A; in particular X ３ and X ４ are the same or different and represent DL, DV, or DA; -X ５ represents F or P, in particular DF ​​or DP The lipolytic peptide of claim 1, having one or more of the following:

6. 6. The lipolytic peptide according to claim 1 or 5, which is a peptide of sequence SEQ ID NO: 54, 72, 74, 75 or a salt thereof, wherein one or more of the amino acids forming said peptide are D-amino acid(s); in particular, all of the amino acids forming said peptide are D-amino acids.

7. The N-terminus is -NH ２ or -NHC(O)R ３ wherein R ３ However, (C １ ~C ２０ ) alkyl, especially (C １ ~C １０ ) alkyl; and the C-terminus is —COOH or —C(O)NH ２ The peptide or salt thereof according to any one of claims 1 to 5,

8. The peptide or salt thereof according to any one of claims 1 to 4, which is selected from the group consisting of SEQ ID NOs: 3 to 38, 61, 66, 69, 80 to 87 and any salt thereof.

9. The peptide or salt thereof according to claim 1 or 5, which is selected from the group consisting of SEQ ID NOs: 55 to 60, 62 to 65, 67, 68, 70, 71 and any salt thereof.

10. A cosmetic composition comprising a cosmetically effective amount of the peptide or salt thereof described in any one of claims 1 to 5 together with one or more cosmetically acceptable carriers or excipients.

11. 11. The cosmetic composition of claim 10, further comprising one or more of an additional lipolytic agent, a vasoprotectant or vasodilator, retinol, a sunscreen, a vitamin, an alpha-hydroxy acid, a surfactant, a dye, a fragrance, and a pigment.

12. The cosmetic composition of claim 10, which is a topical or injectable cosmetic composition.

13. 11. The cosmetic composition of claim 10, which is a topical composition selected from solutions, aerosol and non-aerosol sprays, shaving creams, powders, mousses, lotions, gels, sticks, ointments, pastes, creams, shampoos, shower gels, body washes, or facial cleansers.

14. The cosmetic composition according to claim 10, which is an injectable cosmetic composition, preferably a subcutaneously injectable composition, selected from a solution, a gel or a hydrogel.

15. A pharmaceutical composition comprising a therapeutically effective amount of the peptide or salt thereof according to any one of claims 1 to 5, together with one or more pharmaceutically acceptable carriers or excipients.

16. Use of a peptide according to any one of claims 1 to 5 as a lipid-lowering agent, in particular as a lipolytic agent.

17. Use of a peptide described in any one of claims 1 to 5 in cosmetics.

18. A peptide according to any one of claims 1 to 5 for use in therapy.

19. 10. Use of a cosmetically effective amount of a peptide according to any one of claims 1 to 5 in improving the physical appearance of a mammal having lost or accumulated subcutaneous fat within the fibrous connective tissue beneath the skin.

20. A peptide according to any one of claims 1 to 5 for use in the treatment of conditions caused by or associated with the accumulation of fat in the internal organs.