EP4362904A1

EP4362904A1 - Cosmetic, non-therapeutic uses of peptides

Info

Publication number: EP4362904A1
Application number: EP22748069.6A
Authority: EP
Inventors: Garcia CONSUELO; Xiang-hua QU
Original assignee: Lubrizol Advanced Materials Inc
Current assignee: Lubrizol Advanced Materials Inc
Priority date: 2021-07-02
Filing date: 2022-06-30
Publication date: 2024-05-08
Also published as: WO2023275811A1; CN117642150A

Abstract

The invention relates to the cosmetic, non-therapeutic treatment of skin and, in particular to the use of a compound (R₁- AA₁ -AA₂-AA₃-AA₄-AA₅-AA₆-R₂) for increasing the energy metabolism and/or energy production in skin cells; improving and/or increasing skin radiance; and/or reducing and/or preventing of the symptoms of skin fatigue.

Description

COSMETIC, NON-THERAPEUTIC USES OF PEPTIDES

FIELD OF THE INVENTION

The invention relates to the cosmetic treatment and/or care of the skin. In particular, the invention relates to the use of compounds that are effective in increasing the energy of skin cells and to the use of the compounds for promoting skin radiance and/or as antiskin fatigue agents.

BACKGROUND OF THE INVENTION

The face plays a key role in social perception. Sleep deprivation, stress, disease, and physical or mental exertion affect fatigue and facial cues, and the desire to look less fatigued is one of the primary motivators for undergoing cosmetic treatments.

Skin cells, like all the other cells of the body, are the site of bioenergetic metabolic processes. The energy necessary for all cell functions (macromolecule synthesis, multiplication, defense, signaling, etc.) can be derived from ATP, the classic intracellular energy source, or it can be derived from an exterior source. Skin has a high energy requirement in order to support its metabolic needs, constant tissue regeneration and the repair that is necessary for normal tissue maintenance. UV irradiation exposure to the skin and other external factors that generate ROS (reactive oxidative species) cause harmful changes to (mitochondrial) DNA, cellular membranes, catalytic and structural proteins (e.g. collagen). Human skin cells, that are directly exposed to environmental factors such as sunlight, are highly dependent on large amounts of energy in order to combat cellular deregulation and/or damage. Deficiencies in cutaneous energy capacity are closely related to striking alterations in the structure of human skin. If the skin's repair mechanisms cannot keep pace, detrimental changes in skin structure can occur, leading to a skin looking dull and less healthy.

Mitochondria are the batteries for energy production in the cells and play a vital role in the skin. While the energy requirement may not be as great as other organs, such as skeletal muscle, energy is still integral for processes such as cell signaling, wound healing, pigmentation and vasculature homeostasis [Stout, S. and Birch-Machin,M ‘Mitochondria’s Role in Skin Ageing’, Biology (Basel). 2019 Jun; 8(2): 29] Data shows that human skin cells that are energetically balanced, are metabolically reactivated and thus markedly protected against structural changes of human skin [Blatt T, et al. ‘Stimulation of skin's energy metabolism provides multiple benefits for mature human skin’. Biofactors. 2005;25(1-4):179-85].

W02019008452A1 discloses the use of specific peptides for energizing the skin and preventing the symptoms of skin fatigue. However, there is a need for alternative or improved ways to the provide these cosmetic effects to the skin. There is a need for other compounds that are active in this respect.

It is an object of the present invention to address some of the above-mentioned problems or meet the some of the above-mentioned needs.

SUMMARY OF THE INVENTION

According to a first aspect, the invention provides the use of a compound of formula (I) Ri- AA1-AA2-AA3-AA4-AA5-AA6-R2 (I), a stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AAi is Arg or Lys;

AA2 is Arg or Lys;

AA₃ is Gin, Glu, Asn or Asp;

AA4 is Met or Leu;

AA₅ is Glu, Asp or Gin;

AAb is Glu, Asp or Gin;

Ri is selected from the group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl and R5-CO-, wherein l¾ is selected from the group consisting of H, a non- cyclic aliphatic group, alicyclyl, aryl, aralkyl, heterocyclyl and heteroarylalkyl;

R2 is selected from the group consisting of-NRsRi, -OR₃, -SRB, wherein R3 and R4 are independently selected from a group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and Ri and R2 are not amino acids, for the cosmetic non-therapeutic treatment and/or care of the skin, wherein said cosmetic non-therapeutic treatment and/or care is: increasing the energy metabolism and/or energy production in skin cells; improving and/or increasing skin radiance; and/or reducing and/or preventing skin fatigue. It has been found that the compounds of formula (I) are effective at energising skin cells, improving skin radiance and/or as anti-skin fatigue agents. Advantageously, the compounds are relatively small (6 amino acids) and therefore can be prepared more efficiently than other cosmetically active agents.

According to another aspect, the invention provides a method of cosmetic, non- therapeutic treatment and/or care of the skin of a subject comprising administering a cosmetically effective amount of a compound of formula (I)

Ri- AA1-AA2-AA3-AA4-AA5-AA6-R2 (I), a stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AAi is Arg or Lys;

AA₂ is Arg or Lys;

AA3 is Gin, Glu, Asn or Asp;

AA4 is Met or Leu;

AA₅ is Glu, Asp or Gin;

AA₆ is Glu, Asp or Gin;

Ri is selected from the group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl and R5-CO-, wherein Rs is selected from the group consisting of H, a non- cyclic aliphatic group, alicyclyl, aryl, aralkyl, heterocyclyl and heteroarylalkyl;

R₂ is selected from the group consisting of-NReRi, -OR₃.-SR₃, wherein R₃ and R₄ are independently selected from a group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and Ri and R2 are not amino acids, to the subject, wherein the cosmetic, non-therapeutic treatment and/or care is: increasing the energy metabolism and/or energy production in skin cells; improving and/or increasing skin radiance; and/or reducing and/or preventing skin fatigue.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In the context of this invention “skin” is understood to be the layers which comprise it, from the uppermost layer or stratum corneumtothe lowermost layer or hypodermis, both inclusive. These layers are composed of different types of cells such as keratinocytes, fibroblasts, melanocytes, mast cells, neurones and/or adipocytes among others. The term “skin” also comprises the scalp. The term “skin" includes the skin of mammals and includes human skin. In the context of this invention, skin includes the skin of the whole body including the skin of the face (including skin around the eyes), neckline, neck, decolletage, arms, hands, legs, feet, thighs, hips, buttocks, stomach and torso.

The terms “cosmetic, non-therapeutic treatment” and “care” as used herein has the aim of improving or maintaining the aesthetic appearance of the skin. In particular, the treatment can have the aim of improving cosmetic properties of the skin. The term “care” in the context of this specification refers to the maintenance of properties of the skin. Said properties are subject to being improved or maintained by cosmetic treatment and/or care of the skin both in healthy subjects as well as in those which present diseases and/or disorders of the skin.

In this description, the abbreviations used for amino acids follow the rules of lUPAC-IUB Commission of Biochemical Nomenclature specified in Eur. J. Biochem., (1984), 138, 9-37. Thus, for example, Gly represents NH2-CH2-COOH, Gly- represents NH2-CH2- CO-, -Gly represents -NH-CH2-COOH and -Gly- represents -NH-CH2-CO-. Therefore, the hyphen, which represents the peptide bond, eliminates the OH in the 1 -carboxyl group of the amino acid (represented here in the conventional non-ionized form) when situated to the right of the symbol, and eliminates the H of the 2-amino group of the amino acid when situated to the left of the symbol; both modifications can be applied to the same symbol (see Table 1).

Table 1. Structures of the amino acid residues, their nomenclature in three-letter code and nomenclature for the amino acids in one letter code

Name Residue Symbol Residue

Arginyl Lysyl

-Arg- -Lys-

R K

Glutaminyl Glutamyl

-Gln- -Glu-

Q E Asparaginyl Methionyl

-Asn- -Met-

N M

Leucyl Aspartyl

-Leu- -Asp-

L D

Table 1

As used herein, the term “non-cyclic aliphatic group” includes linear (i.e. straight and unbranched) or branched, saturated or unsaturated hydrocarbyl groups such as alkyl, alkenyl and alkynyl. The non-cyclic aliphatic group may be substituted (mono- or poly- ) or unsubstituted.

As used herein, the term “alkyl” includes both saturated linear and branched alkyl groups, which may be substituted (mono- or poly-) or unsubstituted. The alkyl group is bound to the rest of the molecule by a single bond. The alkyl group has from 1 to 24, preferably from 1 to 16, more preferably from 1 to 14, even more preferably from 1 to 12, yet more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms. The term “alkyl” includes, for example, methyl, ethyl, isopropyl, isobutyl, tert- butyl, 2-methylbutyl, heptyl, 5-methylhexyl, 2-ethylhexyl, octyl, decyl, dodecyl, lauryl, hexadecyl, octadecyl and amyl.

As used herein, the term “alkenyl” refers to a group containing one or more double carbon-carbon bonds and which may be linear or branched and substituted (mono- or poly-) or unsubstituted. Preferably it has 1 , 2 or 3 double carbon-carbon bonds. If more than one double carbon-carbon bond is present, the double bonds may be conjugated or not conjugated. Preferably the alkenyl group has from 2 to 24, preferably from 2 to 16, more preferably from 2 to 14, even more preferably from 2 to 12, yet more preferably 2, 3, 4, 5 or 6 carbon atoms. The alkenyl group is bound to the rest of the molecule by a single bond. The term “alkenyl” includes, for example, vinyl (-CH2=CH2), allyl (-CH2- CH=CH ), prenyl, oleyl, linoleyl groups and similar.

The term “alkynyl” refers to a group containing one or more triple carbon-carbon bonds and which may be linear or branched, and substituted (mono- or poly-) or unsubstituted. Preferably the alkynyl group has 1 , 2 or 3 triple carbon-carbon bonds. The triple bonds may be conjugated or not conjugated The alkynyl group has from 2 to 24, preferably from 2 to 16, more preferably from 2 to 14, even more preferably from 2 to 12, yet more preferably 2, 3, 4, 5 or 6 carbon atoms. The alkynyl group is bound to the rest of the molecule by a single bond. The term “alkynyl” includes, for example and not restricted to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, such as

1 -pentynyl, and similar. The alkynyl group can also contain one or more double carbon- carbon bonds, and alkynyl groups include, for example and not restricted to, but-1-en-3- ynyl and pent-4-en-1-ynyl groups, and similar.

The term “alicyclyl” is used herein to cover, for example and not restricted to, aliphatic cyclic (alicyclic) groups such as cycloalkyl or cycloalkenyl or cycloalkynyl groups. The term "alicyclyl" refers to a monoradical that contains one or more rings of carbon atoms, the rings may be saturated (e.g., cyclohexyl) or unsaturated (e.g., cyclohexenyl) provided that they are not aromatic. More specifically alicylic groups contain three or more, from 3 to 24, from 3 to 12, or from 6 to 12, ring carbon atoms. The alicyclic group may be a monocyclic, bicyclic, or tricyclic ring system and the rings may be, for example, fused or linked by a single bond or a linking group such as a methylene or other alkylene group. The alicyclic group may be substituted (mono- or poly-) or unsubstituted. In one embodiment, the alicyclyl group is a 6 to 12 membered ring system which consists of carbon atoms and optionally contains one or two double bonds.

The term “cycloalkyl” refers to a saturated mono- or polycyclic alkyl group which may be substituted (mono- or poly-) or unsubstituted. The cycloalkyl group has from 3 to 24, preferably from 3 to 16, more preferably from 3 to 14, even more preferably from 3 to 12, yet even more preferably 3, 4, 5 or 6 carbon atoms. The cycloalkyl group is bound to the rest of the molecule by a single bond. Cycloalkyl groups include, for example and not restricted to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl cyclohexyl, dimethyl cyclohexyl, octahydroindene, decahydronaphthalene, dodecahydrophenalene and similar.

The term “cycloalkenyl” refers to a non-aromatic mono- or polycyclic alkenyl group which may be substituted (mono- or poly-) or unsubstituted. The cycloalkenyl group has from 5 to 24, preferably from 5 to 16, more preferably from 5 to 14, even more preferably from 5 to 12, yet more preferably 5 or 6 carbon atoms. The cycloalkenyl group is bound to the rest of the molecule by a single bond. Preferably the cycloalkenyl group contains 1 ,

2 or 3 double carbon-carbon bonds. If more than one double carbon-carbon bond is present, the double bonds may be conjugated or not conjugated. Cycloalkenyl groups include, for example and not restricted to, the cyclopent-1-en-1-yl group and similar.

The term “cycloalkynyl” refers to a non-aromatic mono- or polycyclic alkynyl group which may be substituted (mono- or poly-) or unsubstituted. The cycloalkynyl group has from 8 to 24, preferably from 8 to 16, more preferably from 8 to 14, even more preferably from 8 to 12, yet even more preferably 8 or 9 carbon atoms and is bound to the rest of the molecule by a single bond. Preferably the cycloalkynyl group contains 1, 2 or 3 triple carbon-carbon bonds, conjugated or not conjugated. Cycloalkynyl groups include, for example and not restricted to, the cyclooct-2-yn-1 -yl group and similar. Cycloalkynyl groups can also contain one or more double carbon-carbon bonds, including, for example and not restricted to, the cyclooct-4-en-2-ynyl group and similar.

As used herein, the term “heterocyclyl” or “heterocyclic” refers to a hydrocarbon ring system of 3 to 10 members, wherein one or more of the atoms in the ring or rings is a heteroatom (i.e. not a carbon atom). Thus “heterocyclyl” or “heterocyclic” refers a cyclic group in which the ring atoms consist of carbon and one or more heteroatoms. To satisfy valence, the heteroatom may be bonded to H or substituent groups. Preferably from 1 , 2 or 3 of the ring carbon atoms are heteroatoms. Each heteroatom can be independently selected from the group consisting of O, N, S, P and B, or the group consisting of O, N, and S. The heterocyclyl group may be substituted (mono- or poly-) or unsubstituted. The heterocyclyl group may be a monocyclic, bicyclic, or tricyclic ring system and the rings may be, for example, fused or linked by a single bond or a linking group such as a methylene or other alkylene group. Nitrogen, carbon or sulfur atoms present in the heterocyclyl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heterocyclyl radical may be unsaturated or partially or fully saturated. The heterocyclyl radical may be aliphatic or aromatic. In one embodiment, the heterocyclyl is aliphatic (also known as heteroalicyclyl) and is a 3 to 10 membered ring system where the atoms of the ring or rings consist of carbon atoms and from 1 to 4, or 1 , 2 or 3 heteroatoms. In one embodiment, the heterocyclyl group is a 6 to 10 membered ring system where the atoms of the ring or rings consist of carbon atoms and from 1 to 4 heteroatoms and where the ring system optionally contains one or two double bonds. In one embodiment, the heterocyclyl is aromatic (also known as heteroaryl) and is a 6 to 10 membered ring system where the atoms of the ring or rings consist of carbon atoms and from 1 to 4, or 1 , 2 or 3 heteroatoms. The greatest preference is for the term heterocyclyl to refer to a ring of 5 or 6 members. Examples of saturated heteroalicyclyl groups are dioxane, piperidine, piperazine, pyrrolidine, morpholine and thiomorpholine. Examples of aromatic heterocyclyl groups are pyridine, pyrrol, furan, thiophene, benzofuran, imidazoline, quinolein, quinoline, pyridazine and naphthyridine.

The term “aryl group” refers to an aromatic group which has from 6 to 30, preferably from 6 to 18, more preferably between 6 and 10, yet even more preferably 6 or 10 carbon atoms. The aryl group can comprise 1 , 2, 3 or 4 aromatic rings, which may be linked by a carbon-carbon bond or fused together and includes, for example and not restricted to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or antranyl among others. The aryl group may be substituted (mono- or poly-) or unsubstituted.

The term “aralkyl group” refers to an alkyl group substituted by an aromatic group, with from 7 to 24 carbon atoms and including, for example and not restricted to, -(CH2)i-6-phenyl, -(CH₂)I-₆-(1 -naphthyl), -(CH₂)i-₆-(2-naphthyl), -(CH2)i-6-CH(phenyl)2 and similar.

The term “heteroarylalkyl” refers to an alkyl group substituted by a heteroaryl (also known as aromatic heterocyclic) group as defined above, the alkyl group having from 1 to 6 carbon atoms and the heteroaryl group having from 2 to 24 carbon atoms and from 1 to 3 heteroatoms. Heteroarylalkyl groups include, for example and not restricted to, -(CH2)i-6-imidazolyl, -(CH2)i-6-triazolyl, -(CH2)i-6-thienyl, -(CH2)i-6-furyl, -(CH2)i-6-pyrr olidinyl and similar.

As is understood in this technical field, there may be a certain degree of substitution of the aforementioned groups. In particular, there can be substitution in any of the groups identified above where it is explicitly stated. The substituted groups (radicals) referred to above are groups (or radicals) which are substituted in one or more positions available by one or more substituents. Preferably substitution is in the 1 , 2 or 3 positions, more preferably in the 1 or 2 positions, yet even more preferably in the 1 position. Suitable substituents include, for example and not restricted to: C1-C4 alkyl; hydroxyl; C1-C4 alkoxyl; amino; amino-Ci-C4alkyl; Ci-C₄carbonyloxyl; C1-C4 oxycarbonyl; halogen such as fluoride, chlorine, bromine and iodine; cyano; nitro; azide; C1-C4 alkylsulfonyl; thiol; C1-C4 alkylthio; aryloxy such as phenoxyl; -NRb(C=NRb)NR Rc; wherein R_b and Rc are independently selected from the group formed by H, C1-C4 alkyl, C2-C4 alkenyl, alkynyl, C3-C10 cycloalkyl, C₆-Ciearyl, C7-C17 aralkyl, heterocyclyl of 3-10 members or protective group of the amino group. As used herein, the term “comprising”, which is inclusive or open-ended and does not exclude additional unrecited elements or method steps, is intended to encompass as alternative embodiments, the phrases “consisting essentially of’ and “consisting of’ where “consisting of excludes any element or step not specified and “consisting essentially of permits the inclusion of additional unrecited elements or steps that do not materially affect the essential or basic and novel characteristics of the composition or method under consideration. Cosmetic Use

This invention is based on the finding of surprising cosmetic, non-therapeutic properties of compounds of formula (I). Compounds of formula (I), including all the embodiments of formula (I) disclosed herein, are also referred to herein as compounds of the invention. It has been discovered that compounds of formula (I) are able to increase the energy of skin cells. In particular, it has been found that compounds of formula (I) are able to increase the mitochondrial potential of human dermal fibroblasts skin cells. It is believed that, as a result, compounds of formula (I) are able to cause a higher production of energy in skin cells. The terms “increase in the energy”, “increase of energy metabolism” and/or “increase of energy production in skin cells” as used herein refer to an increase in the supply of energy to skin (i.e. cutaneous) cells. The compounds of formula (I) can enable an increase in the energy supply to the cells through an increase of the mitochondrial membrane potential. An increase of the energy metabolism of the skin cells improves skin function. Thus, the compounds of formula (I) promote a healthy appearance of the skin. The invention relates to the use of compounds of formula (I) for the cosmetic, non- therapeutic treatment and/or care of the skin, wherein said cosmetic, non-therapeutic treatment and/or care is the increase of energy metabolism and/or energy production in skin cells. It has also been found that the compounds of formula (I) can be used to improve and/or increase skin radiance. Skin radiance is a vibrant look associated with healthy, well- rested skin. Skin radiance is the ability of the skin to reflect light and is referred to in terms of “gloss” of the skin. Skin with high gloss reflects more light and and thus has better or more radiance that skin of low gloss. As used herein, improving and/or increasing skin radiance means an improvement of the physical appearance of the skin by an improvement in the natural gloss of the skin. The invention relates to the use of compounds of formula (I) for the cosmetic, non-therapeutic treatment and/or care of the skin, wherein said cosmetic, non-therapeutic treatment and/or care is the improvement and/or increase of skin radiance.

Further, it has been found that the compounds of formula (I) can be used as anti-skin fatigue agents. The compounds of formula (I) can be used for reducing and/or preventing skin fatigue. .Skin fatigue is also known as “skin tiredness” Skin tiredness can be measured by determining the “tiring effects” of the skin, for instance by determining the standard R9 parameter with a Cutometer® MPA 580 from Courage+Khazaka electronic GmbH , where R9 represents the tiring effects of the skin after repeated sucking. The smaller the R9 value, the smaller the tiring effects and thus the lower skin fatigue. The compounds of formula (I) can be used for reducing and/or preventing tiring effects of the skin. The invention relates to the use of compounds of formula (I) for the cosmetic, non- therapeutic treatment and/or care of the skin, wherein said cosmetic, non-therapeutic treatment and/or care is the reduction and/or prevention skin fatigue.

Compound of formula (I)

The invention relates to cosmetic, non-therapeutic uses of and methods of treatment and/or care employing a compound of formula (I)

Ri- AAi -AA2-AA3-AA4-AA5-AA6-R2 (I), a stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AAi is Arg or Lys;

AA2 is Arg or Lys;

AA₃ is Gin, Glu, Asn or Asp;

AA4 is Met or Leu;

AA₅ is Glu, Asp or Gin;

AAe is Glu, Asp or Gin;

R2 is selected from the group consisting of-NRjRi, -OR3.-SR3, wherein R3 and R4 are independently selected from a group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and Ri and R2 are not amino acids. In the compound of formula (I), Ri is bound to the amino terminal end (N-terminal) of the peptide and F¾ is bound to the carboxy-terminal end (C-terminal) of the peptide. Ri can be selected from the group consisting of H, a polymer derived from polyethylene glycol with a molecular weight comprised between 200 and 35000 Daltons and R5-CO-, wherein R₅ is selected from the group consisting of C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C24 cycloalkyl, C5-C24 cycloalkenyl, C8-C24 cycloalkynyl, C6-C30 aryl, C7-C24 aralkyl, 3-10 membered heterocyclyl ring, and a heteroarylalkyl containing from 2 to 24 carbon atoms and from 1 to 3 heteroatoms, wherein the alkyl group has 1 to 6 carbon atoms.

Ri can be selected from the group consisting of H and R5-CO-, wherein R₅ is selected from the group consisting of C1-C18 alkyl, C2-C24 alkenyl, C3-C24 cycloalkyl or the group consisting of C1-C16 alkyl, C2-C18 alkenyl, C3-C7 cycloalkyl. The R5-CO- group includes alkanoyl groups such as acetyl (CH3-CO-, which is abbreviated herein as “Ac-”), myristoyl (CH₃-(CH₂)i2-CO-, which is abbreviated herein as “Myr-“) and palmitoyl (CH3-(CH )i4-CO-, which is abbreviated herein as “Palm-"). Ri can be selected from the group consisting of H and acetyl, ferf-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.

Ri can be selected from the group consisting of H and R5-CO-, wherein R₅ is selected from the group consisting of C1-C16 alkyl or C2-C18 alkenyl.

Ri can be selected from the group consisting of H and R5-CO-, wherein Rs is C1-C15 alkyl.

Ri can be selected from the group consisting of H, acetyl and palmitoyl.

R2 can be selected from the group consisting of -NR3R4, -OR3, -SR3, wherein R3 and R4 are independently selected from the group formed by H, a polymer derived from polyethylene glycol, C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C24 cycloalkyl, C5-C24 cycloalkenyl, C8-C24 cycloalkynyl, C6-C3oaryl, C7-C24 aralkyl, 3-10 membered heterocyclyl ring, and heteroarylalkyl containing from 2 to 24 carbon atoms and from 1 to 3 heteroatoms, wherein the alkyl group has 1 to 6 carbon atoms. Optionally, R3 and R4 can be joined by a saturated or unsaturated carbon-carbon bond, forming a ring with the nitrogen atom.

(¾ can be -NR3R4 or -OR3. R3 and R4 can be independently selected from the group consisting of H, a polymer derived from polyethylene glycol with a molecular weight comprised between 200 and 35000 Daltons, methyl, ethyl, hexyl, dodecyl and hexadecyl. Alternatively, R3 and R can be independently selected from the group consisting of H and C1-C16 alkyl. In one embodiment, R2 is not OR3 where R3 is a methyl group, i.e. R2 is not OCH3. In one embodiment R3 is H and R4 is selected from the group formed by H and C1-C16 alkyl, including methyl, ethyl, hexyl, dodecyl and hexadecyl.

R2 can be selected from the group consisting of -OH, -NH2and -NHR4 where R* is C1-C16 alkyl or C1-C3 alkyl or C1-C2 alkyl.

R2 can be -OH or -NH2.

Ri can be selected from the group consisting of H and R5-CO-, wherein R5 is selected from the group consisting of C1-C18 alkyl, C2-C24 alkenyl, C3-C24 cycloalkyl; and R2 is -NR3R4 or -OR3 wherein R3 and R4 are independently selected from the group consisting of H and Ci-Ci6alkyl. In this embodiment, R3 can be H and R4 can be selected from the group formed by H, C1-C16 alkyl, C1-C3 alkyl and C1-C2 alkyl; for example, R2 can be selected from the group consisting of -OH and -NH2.

Ri can be selected from the group consisting of H and acetyl, ferf-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl; and R2 is -NR3R4 or -OR3 wherein R3 and R4 are independently selected from the group consisting of H and C1-C16 alkyl. In this embodiment, R3 can be H and R4 can selected from the group formed by H, C1-C16 alkyl, C1-C3 alkyl and C1-C2 alkyl; for example, R2 can be selected from the group consisting of -OH and -NH2.

Ri can be selected from the group consisting of H and R5-CO-, wherein R5 is selected from the group consisting of C1-C16 alkyl or C2-C18 alkenyl; and R2 is -NR3R4 or -OR3 wherein R3 and R4 are independently selected from the group consisting of H and C1-C16 alkyl. In this embodiment R3 can be H and i can be selected from the group formed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, F¾ can be selected from the group consisting of -OH and -NH2.

Ri can be selected from the group consisting of H, acetyl, myristoyl or palmitoyl; and F¾ is -NR₃R₄ or -OR₃ wherein R₃ and R₄ are independently selected from the group consisting of H and CrCi₆alkyl. In this embodiment R₃ can be H and R₄ can be selected from the group formed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂ can be selected from the group consisting of -OH and -NH₂.

Ri can be selected from the group consisting of H and R₅-CO-, wherein R₅ is C₁-C₁₅ alkyl and R₂ is -NR₃R₄ or -OR₃ wherein l¾ and l¾ are independently selected from the group consisting of H and Ci-Ci₆alkyl. In this embodiment R₃ can be H and R₄ can be selected from the group formed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂ can be selected from the group consisting of -OH and -NH₂.

Ri can be selected from the group consisting of H, acetyl and palmitoyl and R₂ is -NR₃R₄ or -OR₃ wherein R₃ and R₄ are independently selected from the group consisting of H and C₁-C₁₆ alkyl. In this embodiment R₃ can be H and R₄ can be selected from the group formed by H, C₁-C₁₆ alkyl, C₁-C₃ alkyl and C₁-C₂ alkyl; for example, R₂ can be selected from the group consisting of -OH and -NH₂.

Ri can be selected from the group consisting of a substituted non-cyclic aliphatic group, substituted alicyclyl, substituted heterocyclyl, substituted heteroarylalkyl, substituted aryl, substituted aralkyl and R₅-CO-, wherein R₅ is selected from the group consisting of a substituted non-cyclic aliphatic group, substituted alicyclyl, substituted aryl, substituted aralkyl, substituted heterocyclyl and substituted heteroarylalkyl; and/or R₂ is -NR₃R₄, wherein at least one of R3 and R4 is selected from the group consisting of a substituted non-cyclic aliphatic group, substituted alicyclyl, substituted heterocyclyl, substituted heteroarylalkyl, substituted aryl and substituted aralkyl, or R is -OR₃, or -SR₃, wherein R3 is selected from the group consisting of a substituted non-cyclic aliphatic group, substituted alicyclyl, substituted heterocyclyl, substituted heteroarylalkyl, substituted aryl and substituted aralkyl.

The most preferred structures of the polymer derived from polyethylene glycol are the group (-CH₂-CH₂-0)rH in which r is a number comprised between 4 and 795 and the group where s is a number comprised between 1 and 125.

The compound of formula (I) can be such that at least one of: Ri is not H; and F¾ is not OH. That is, the compound of formula (I) can be such that Ri is not H and/or R2 is not OH.

The compound of formula (I) can be such that: AAi is selected from the group consisting of Arg and Lys; AA2 is selected from the group consisting of Arg and Lys; AA3 is selected from the group consisting of Gin and Asp; AA4 is selected from the group consisting of Met and Leu; AA5 is selected from the group consisting of Glu and Asp; and AAb is selected from the group consisting of Glu and Gin. Preferably, AAi is Arg and/or AA₂ is Arg. The compound of formula (I) can be such that: AAi is selected from the group consisting of Arg and Lys; AA2 is selected from the group consisting of Arg and Lys; AA3 is Gin; AA4 is Met; AA5 is selected from the group consisting of Glu and Asp; and AAb is selected from the group consisting of Glu and Gin. Preferably, AAi is Arg and/or AA2 is Arg. The compound of formula (I) can be such that: AAi is selected from the group consisting of Arg and Lys; AA2 is selected from the group consisting of Arg and Lys; AA3 is selected from the group consisting of Gin and Asp; AA4 is selected from the group consisting of Met and Leu; AA₅is selected from the group consisting of Glu, Asp and Gin; and AAe is selected from the group consisting of Glu, Gin and Asp. Preferably AAi is Arg and/or AA2 is Arg.

The compound of formula (I) can be such that: AAi is selected from the group consisting of Arg and Lys; AA2 is selected from the group consisting of Arg and Lys; AA₃ is selected from the group consisting of Gin and Glu; AA4 is selected from the group consisting of Met and Leu; AA₅is selected from the group consisting of Glu, Asp and Gin; and AAb is selected from the group consisting of Glu, Gin and Asp. Preferably AAi is Arg and/or AA2 is Arg. The compound of formula (I) can be such that: AAi is selected from the group consisting of Arg and Lys; AA2 is selected from the group consisting of Arg and Lys; AA3 is selected from the group consisting of Gin, Glu, Asn and Asp or the group consisting of Gin and Asp; AA * is selected from the group consisting of Met and Leu; AA5 is selected from the group consisting of Glu and Gin; and AAe is is selected from the group consisting of Glu and Gin. Preferably, AAi is Arg and/or AA2 is Arg.

The compound of formula (I) can be such that: AAi is Arg; AA2 is selected from the group consisting of Arg and Lys; AA₃ is selected from the group consisting of Gin and Asp; AA4 is selected from the group consisting of Met and Leu; AA₅ is Glu; and AAb is Glu. Preferably, AA2 is Arg.

The compound of formula (I) can be such that: AAi is selected from the group consisting of Arg and Lys; AA2 is Arg; AA3 is Gin; AA* is Met; AA5 is selected from the group consisting of Glu and Asp; and AAb is selected from the group consisting of Glu and Gin. Preferably, AAi is Arg.

The compound of formula (I) can be such that: AAi is Arg; AA₂ is Arg; AA3 is Gin; AA is Met; AA5 is Glu; and AAe is Glu; and 0, 1, 2, 3 or 4 of AAi, AA2, AA3, AA4, AA5 and AAe are replaced providing that: when AA^ is replaced, it is replaced by Lys; when AA2 is replaced, it is replaced by Lys; when AA3 is replaced, it is replaced by Glu, Asn or Asp; when AA4 is replaced, it is replaced by Leu; when AAs is replaced, it is replaced by Asp or Gin; and when AAe is replaced, it is replaced by Asp or Gin. In one embodiment, 0, 1 , 2 or 3 of AAi, AA2, AA3, AA₄, AA₅ and AAe are replaced. In one embodiment, 0 (none) of AAi, AA2, AA3, AA₄, AA5 and AAb is replaced. In one embodiment, one of AAi, AA2, AA3, AA4, AA5 and AAb is replaced. In one embodiment, two of AAi, AA2, AA3, AAt, AA5 and AAb are replaced. In one embodiment, three of AAi, AA2, AA3, AA , AAs and AAb are replaced.

The compound of formula (I) can be such that: AAi is Arg; AA2 is Arg; AA3 is Gin; AA₄ is Met; AAs is Glu; and AAe is Glu; and 0, 1, 2, 3 or 4 of AAi, AA2, AAB, AA*, AAs and AA_b are replaced providing that: when AAi is replaced, it is replaced by Lys; when AA2 is replaced, it is replaced by Lys; when AA3 is replaced, it is replaced by Glu; when AA₄ is replaced, it is replaced by Leu; when AA5 is replaced, it is replaced by Asp; and when AAe is replaced, it is replaced by Gin. In one embodiment, 0, 1 , 2 or 3 of AAi, AA2, AA3, AA*, AAs and AAb are replaced. In one embodiment, 0 (none) of AAi, AA2, AA3, AA₄, AAs and AAe is replaced. In one embodiment, one of AAi, AA2, AA3, AA4, AA5 and AAe is replaced. In one embodiment, two of AAi, AA2, AA3, AA4, AA₅ and AAe are replaced. In one embodiment, three of AAi, AA2, AA3, AA4, AA5 and AAe are replaced.

The compound of formula (I) can be as described above, wherein each of AAi, AA2, AA₃, AA4, AA5 and AAb in formula (I) is an L-amino acid. This embodiment includes a compound of formula (I) wherein: AAi is L-Arg; AA2 is L-Arg; AA3 is L-Gln; AA4 is L-Met; AAs is L-Glu; and AAe is L-Glu.

The compound of formula (I) can be such that at least one of AAi, AA , AA3, AA4, AA5 and AAe in formula (I) is a D-amino acid. This embodiment includes a compound of formula (I), wherein 1 , 2 or 3 of AAi, AA2, AA3, AA4, AAs and AAe in formula (I) is a D- amino acid and the remaining of AAi, AA2, AA3, AA4, AA₅ and AAe are L-amino acids. For example, a compound of formula (I) where 1, 2, or 3 of AA3, AA* and AA5 are D- amino acids and the other amino acids, i.e. the remaining of AAi to AAe, are L-amino acids. This embodiment includes where 1 or 2 of AA3, AA4 and AA5 are D-amino acids and the other amino acids, i.e the remaining of AAi to AAe, are L-amino acids. This embodiment includes, for example, a compound of formula (I), where AA* is a D-amino acid and each of AAi, AAå, AA3, AAs and AAe is an L-amino acid. These embodiments of the invention apply to all the embodiments of the compound of formula (I) described herein in which none of the amino acids AAi, AA2, AA3, AA4, AAs and AAe is assigned as a D- or an L- amino acid.

Thus the compound of formula (I) can be such that: AAi is selected from the group consisting of Arg and Lys; AA2 is selected from the group consisting of Arg and Lys; AA3 is selected from the group consisting of Gin and Asp; AA4 is selected from the group consisting of Met and Leu; AAs is selected from the group consisting of Glu and Asp; and AAb is selected from the group consisting of Glu and Gin, and 1, 2, or 3 of AA₃, AA4and AAs are D-amino acids and the other amino acids, i.e. the remaining of AAi to AAb, are L-amino acids. This embodiment includes where 1 or2 of AA3, AA4and AAs are D-amino acids and the other amino acids, i.e. the remaining of AAi to AAe, are L-amino acids. This embodiment includes where AA* is a D-amino acid and each of AAi, AA2, AA3, AAs and AAe is an L-amino acid.

The compound of formula (I) can be such that: AAi is Arg; AA2 is Arg; AAB is Gin; AA4 is Met; AAs is Glu; and AAs is Glu; and 0, 1, 2, 3 or 4 of AAi, AA₂, AA3, AA4, AAs and AAs are replaced providing that: when AAi is replaced, it is replaced by Lys; when AA2 is replaced, it is replaced by Lys; when AA₃ is replaced, it is replaced by Glu, Asn or Asp; when AA4 is replaced, it is replaced by Leu; when AA5 is replaced, it is replaced by Asp or Gin; and when AA is replaced, it is replaced by Asp or Gin, and 1 , 2, or 3 of AA3, AA4 and AA5 are D-amino acids and the other amino acids, i.e. the remaining of AAi to AAb, are L-amino acids. This embodiment includes where 1 or 2 of AA3, AAiand AA5 are D- amino acids and the other amino acids, i.e the remaining of AAi to AAe, are L-amino acids. This embodiment includes where AA is a D-amino acid and each of AAi, AA¾ AA3, AA5 and AA is an L-amino acid. 0, 1 , 2 or 3 of AAi, AA2, AA3, AA4, AA5 and AA can be replaced. 0 (none) of AAi, AA₂, AA₃, AA4, AA5 and AA₆ can be replaced. One of AAi, AA₂, AAB, AA4, AA5 and AA₆ can be replaced. Two of AAi, AA₂, AA₃, AA4, AA5 and AAe can be replaced. Three of AAi, AA2, AA₃, AA4, AAs and AAb can be replaced.

The compound of formula (I) can be such that: AAi is Arg; AA2 is Arg; AA is Gin; AA4 is Met; AA5 is Glu; and AA is Glu; and 0, 1, 2, 3 or 4 of AAi, AA , AAs, AA4, AA5 and AA are replaced providing that: when AAi is replaced, it is replaced by Lys; when AA2 is replaced, it is replaced by Lys; when AAs is replaced, it is replaced by Glu; when AA4 is replaced, it is replaced by Leu; when AA5 is replaced, it is replaced by Asp; and when AAQ is replaced, it is replaced by Gin, and 1 , 2, or 3 of AAs, AAiand AAs are D-amino acids and the other amino acids, i.e. the remaining of AAi to AA, are L-amino acids. This embodiment includes where 1 or 2 of AA, AAand AA₅ are D-amino acids and the other amino acids, i.e the remaining of AAi to AAs, are L-amino acids. This embodiment includes where AA4 is a D-amino acid and each of AAi, AA2, AA3, AAs and AAs is an L- amino acid. 0, 1 , 2 or 3 of AAi, AA2, AAs, AA_t, AAs and AA₆ can be replaced. 0 (none) of AAi, AA₂, AA_3I AA4, AAs and AA₆ can be replaced. One of AAi, AA₂, AA3, AA_t, AAs and AAb can be replaced. Two of AAi, AA₂, AAs, AA, AA₅ and AA₆ can be replaced. Three of AAi, AA, AA, AA, AA₅ and AA can be replaced.

The compound of formula (I) can be such that: AAi is selected from the group consisting of L-Arg and L-Lys; AA is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of D-Gln, D-Glu, D-Asn and D-Asp or from the group consisting of D-Gln and D-Asp; AA is selected from the group consisting of L-Met and L-Leu; A is selected from the group consisting of L-Glu, L-Asp and L-Gln; and AA is selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, preferably is AAi is L-Arg and AA is L-Arg. This embodiment includes a compound of formula (I) wherein: AAi is L-Arg; AA₂ is L-Arg; AA3 is D-Gln; AA4 is L-Met; AAsis L-Glu; and AAs is L-Glu.

The compound of formula (I) can be such that: AAi is selected from the group consisting of L-Arg and L-Lys; AA₂ is selected from the group consisting of L-Arg and L-Lys; AA₃ is selected from the group consisting of L-Gln, L-Glu, L-Asn and L-Asp or from the group consisting of L-Gln and L-Asp; AA4 is selected from the group consisting of D-Met and D-Leu; AAs is selected from the group consisting of L-Glu, L-Asp and L-Gln; and AAb is selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, preferably is AAi is L-Arg and AA₂ is L-Arg. This embodiment includes a compound of formula (I) wherein: AAi is L-Arg; AA₂ is L-Arg; AA3 is L-Gln; AA4 is D-Met; AAsis L-Glu; and AAe is L-Glu.

The compound of formula (I) can be such that: AAi is selected from the group consisting of L-Arg and L-Lys; AA₂ is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of L-Gln, L-Glu, L-Asn and L-Asp or from the group consisting of L-Gln and L-Asp; AA* is selected from the group consisting of L-Met and L- Leu; AA5 is selected from the group consisting of D-Glu, D-Asp and D-Gln; and AAe is selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, preferably is AAi is L-Arg and AA₂ is L-Arg. This embodiment includes a compound of formula (I) wherein: AAi is L-Arg; AA₂ is L-Arg; AA3 is L-Gln; AA4 is L-Met; AA₅ is D-Glu; and AAb is L-Glu.

The compound of formula (I) can be such that: AAi is selected from the group consisting of L-Arg and L-Lys; AA2 is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of L-Gln, L-Glu, L-Asn and L-Asp or from the group consisting of L-Gln and L-Asp; AA4 is selected from the group consisting of D-Met and D-Leu; AA5 is selected from the group consisting of D-Glu, D-Asp and D-Gln; and AA₆ is selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, preferably is AAi is L-Arg and AA₂ is L-Arg. This embodiment includes a compound of formula (I) wherein: AAi is L-Arg; AA₂ is L-Arg; AA3 is L-Gln; AA4 is D-Met; AAs is D-Glu; and AAb is L-Glu.

The compound of formula (I) can be such that: AAi is selected from the group consisting of L-Arg and L-Lys; AA₂ is selected from the group consisting of L-Arg and L-Lys; AA3 is selected from the group consisting of D-Gln, D-Glu, D-Asn and D-Asp or from the group consisting of D-Gln and D-Asp; AA4 is selected from the group consisting of D-Met and D-Leu; AA5 is selected from the group consisting of L-Glu, L-Asp and L-Gln; and AAb is selected from the group consisting of L-Glu, L-Gln and L-Asp. In this embodiment, preferably is AAi is L-Arg and AA2 is L-Arg. This embodiment includes a compound of formula (I) wherein: AAi is L-Arg; AA2 is L-Arg; AA3 is D-Gln; AA4 is D-Met; AA5 is L-Glu; and AAe is L-Glu.

Compounds of formula (I) include those selected from the group of amino acid sequences listed in Table 2, in which their sequence identifier is detailed, their stereoisomers, and/or their cosmetically or pharmaceutically acceptable salts.

Sequence Identifier

Arg-Arg-Gln-Met-Glu-Glu SEQ ID NO. 1

Arg-Arg-Gln-D-Met-Glu-Glu SEQ ID NO. 2

Arg-Arg-Asp-D-Met-Glu-Glu SEQ ID NO. 3

Arg-Arg-Gln-D-Met-Asp-Glu SEQ ID NO. 4

Arg-Arg-Gln-D-Met-Glu-Gln SEQ ID NO. 5

Arg-Arg-Gln-Leu-Glu-Glu SEQ ID NO. 6

Arg-Arg-Gln-D-Met-Gln-Glu SEQ ID NO. 7

Arg-Arg-Gln-D-Met-Glu-Asp SEQ ID NO. 8

Arg-Lys-Gln-D-Met-Glu-Glu SEQ ID NO. 9

Lys-Arg-Gln-D-Met-Glu-Glu SEQ ID NO. 10

Arg-Arg-D-Gln-Met-Glu-Glu SEQ ID NO. 11

Arg-Arg-Gln-D-Leu-Glu-Glu SEQ ID NO. 12

Arg-Arg-Gln-D-Met-D-Glu-Glu SEQ ID NO. 13

Arg-Arg-D-Gln-D-Met-Glu-Glu SEQ ID NO. 14

Arg-Arg-Asp-D-Met-Asp-Gln SEQ ID NO. 15 Arg-Arg-Asp-D-Leu-Asp-Gln SEQ ID NO. 16 L-Arg-L-Arg-L-GIn-L-Met-L-Glu-L-Glu SEQ ID NO. 17 L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu SEQ ID NO. 18 L-Arg-L-Arg-L-Asp-D-Met-L-Glu-L-Glu SEQ ID NO. 19 L-Arg-L-Arg-L-Gln-D-Met-L-Asp-L-Glu SEQ ID NO. 20 L-Arg- L-Arg-L-Gln-D-Met-L-Glu-L-Gln SEQ ID NO. 21 L-Arg-L-Arg-L-Gln- L-Leu-L-Glu-L-Glu SEQ ID NO. 22 L-Arg-L-Arg- L-Gln-D-Met-L-Gln-L-Glu SEQ ID NO. 23 L-Arg-L-Arg- L-Gln-D-Met-L-Glu- L-Asp SEQ ID NO. 24 L-Arg-L-Lys-L-Gln-D-Met-L-Glu-L-Glu SEQ ID NO. 25 L-Lys-L-Arg-L-Gln-D-Met-L-Glu-L-Glu SEQ ID NO. 26 L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu SEQ ID NO. 27 L-Arg-L-Arg-L-Gln-D-Leu-L-Glu-L-Glu SEQ ID NO. 28 L-Arg-L-Arg-L-Gln-D-Met-D-Glu-L-Glu SEQ ID NO. 29 L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu SEQ ID NO. 30 L-Arg-L-Arg-L-Asp-D-Met-L-Asp-L-GIn SEQ ID NO. 31 L-Arg-L-Arg-L-Asp-D-Leu-L-Asp-L-Gln SEQ ID NO. 32

Table 2

Compounds of formula (I) include each of the sequences of Table 2 in which one of amino acids AAi to AAb is replaced by a replacement amino acid, wherein the replacement amino acid is selected from the alternative amino acids listed for the amino acid being replaced in formula (I) above. The replacement amino acid is different from the amino acid that is being replaced. Thus the invention provides for each of the sequences of Table 2 in which one of amino acids AAi to AAb is replaced by an amino acid, wherein: when an AAi amino acid in one of the sequences in Table 2 is replaced it is replaced by Arg or Lys, with the proviso that if the AAi amino acid is Arg it is replaced by Lys and if the AAi amino acid is Lys it is replaced by Arg; when an AA2 amino acid in one of the sequences in Table 2 is replaced it is replaced by Arg or Lys, with the proviso that if the AA2 amino acid is Arg it is replaced by Lys and if the AA2 amino acid is Lys it is replaced by Arg; when an AA3 amino acid in one of the sequences in Table 2 is replaced it is replaced by Gin, Glu, Asn or Asp, with the proviso that if the AA3 amino acid is Gin it is replaced by Glu, Asn or Asp, if the AA3 amino acid is Glu it is replaced by Gin, Asn or Asp, if the AA3 amino acid is Asn it is replaced by Glu, Gin or Asp, and if the AA3 amino acid is Asp it is replaced by Glu, Gin or Asn; when an AA4 amino acid in one of the sequences in Table 2 is replaced it is replaced by Met or Leu, with the proviso that if the AA4 amino acid is Met it is replaced by Leu and if the AA4 amino acid is Leu it is replaced by Met; when an AA5 amino acid in one of the sequences in Table 2 is replaced it is replaced by Glu, Asp or Gin, with the proviso that if the AA5 amino acid is Gin it is replaced by Glu or Asp, if the AA5 amino acid is Glu it is replaced by Gin or Asp, and if the AA5 amino acid is Asp it is replaced by Glu or Gin; and when an AAe amino acid in one of the sequences in Tables 2 is replaced it is replaced by Glu, Asp or Gin, with the proviso that if the AAe amino acid is Gin it is replaced by Glu or Asp, if the AAb amino acid is Glu it is replaced by Gin or Asp, and if the AAe amino acid is Asp it is replaced by Glu or Gin.

In the amino acid sequences of Table 2 according to formula (1), Ri and f¾ are H and OH, respectively. Compounds of formula (I) include each of the sequences of Table 2 with their N- and C- terminals modified by the other Ri and R2 groups, respectively, as defined herein for formula (1 ). For example, compounds of formula (I) include each of the sequences of Table 2 in which the N-terminal amino acid residue terminates with Ri as defined above for formula (1) where Ri is not H, and, alternatively or additionally, where the C-terminal amino acid residue optionally terminates with R2 as defined above for formula (1) where R2 is not OH.

Thus, in particular, the compound according to formula (i) can be an amino acid sequence selected from SEQ ID NO.s 1, 2, 11, 13, 17, 18, 19, 20, 21 , 25, 26, 27, 28, 29 and 30, or from SEQ ID NO.s 1, 2, 11, 13, 17, 18, 27 and 30, and its stereoisomers, and/or its cosmetically or pharmaceutically acceptable salts, wherein optionally, said sequence has its N-terminal amino acid modified by Ri as defined above for formula (1), where Ri is not H, and, alternatively or additionally, said sequence has its C-terminal amino acid modified by R2 as defined above for formula (1) where R2 is not OH. The amino acid sequence can be SEQ ID NO.s 17, 18, 19, 20, 21, 25, 26, 27, 28, 29 and 30. The amino acid sequence can be SEQ ID NO.s 17, 18, 27 and 30. The amino acid sequence can be SEQ ID NO. 17. The amino acid sequence can be SEQ ID NO. 27. The amino acid sequence can be SEQ ID NO. 18. The amino acid sequence can be SEQ ID NO. 30.

The compounds of formula (I) can exist as stereoisomers or mixtures of stereoisomers; for example, the amino acids which comprise them can have the configuration L-, D-, or be racemic independently of each other. Therefore, it is possible to obtain isomeric mixtures as well as racemic mixtures or diastereomeric mixtures, or pure diastereomers or enantiomers, depending on the number of asymmetric carbons and on which isomers or isomeric mixtures are present. The preferred structures of the compounds of formula (I) are pure isomers, i.e., enantiomers or diastereomers. For example, when it is stated that AA2 can be Arg, it is understood that, unless otherwise specified, AA2 is selected from L-Arg, D-Arg or mixtures of both, racemic or non-racemic. The preparation procedures described in this document enable the person skilled in the art to obtain each of the stereoisomers of the compound by choosing the amino acid with the right configuration.

In the context of this invention, the term "amino acids” includes the amino acids encoded by the genetic code as well as non-encoded amino acids, whether they are natural or not. Examples of non-encoded amino acids are, without restriction, citrulline, ornithine, sarcosine, desmosine, norvaline, 4-aminobutyric acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 6-aminohexanoyc acid, 1-naphthylalanine, 2-naphthylalanine, 2-aminobenzoic acid, 4-aminobenzoic acid, 4-chlorophenylalanine, 2,3- diaminopropionic acid, 2,4-diaminobutyric acid, cycloserine, carnitine, cystine, penicillamine, pyroglutamic acid, thienylalanine, hydroxyproline, allo-isoleucine, allo- threonine, isonipecotic acid, isoserine, phenylglycine, statin, b-alanine, norleucine, N- methyl amino acids, a-amino acids and b-amino acids, among others, as well as their derivatives. A list of non-natural amino acids can be found in the article "Unusual amino acids in peptide synthesis" by D.C. Roberts and F. Vellaccio, in The Peptides, Vol. 5 (1983), Chapter VI, Gross E. and Meienhofer J., Eds., Academic Press, New York, USA or in the commercial catalogues of the companies specialized in the field.

In particular, the compound of formula (I) can be selected from the group of compounds listed in Tables 3, their stereoisomers, and/or their cosmetically acceptable salts.

Table 3

Compounds of the formula (I) include each of the compounds of Table 3 in which one of amino acids AAi to AAe is replaced by a replacement amino acid, wherein the replacement amino acid is selected from the alternative amino acids listed for the amino acid being replaced in formula (I) above. The replacement amino acid is different from the amino acid that is being replaced. Thus the compounds of formula (I) include the compounds of Table 3, in which one of amino acids AAi to AAe is replaced by an amino acid, wherein: when an AAi amino acid in one of the sequences in Table 3 is replaced it is replaced by Arg or Lys, with the proviso that if the AAi amino acid is Arg it is replaced by Lys and if the AAi amino acid is Lys it is replaced by Arg; when an AA2 amino acid in one of the sequences in Table 3 is replaced it is replaced by Arg or Lys, with the proviso that if the AA2 amino acid is Arg it is replaced by Lys and if the AA2 amino acid is Lys it is replaced by Arg; when an AA3 amino acid in one of the sequences in Table 3 is replaced it is replaced by Gin, Glu, Asn or Asp, with the proviso that if the AA3 amino acid is Gin it is replaced by Glu, Asn or Asp, if the AA3 amino acid is Glu it is replaced by Gin, Asn or Asp, if the AA3 amino acid is Asn it is replaced by Glu, Gin or Asp, and if the AA3 amino acid is Asp it is replaced by Glu, Gin or Asn; when an AA4 amino acid in one of the sequences in Table 3 is replaced it is replaced by Met or Leu, with the proviso that if the AA4 amino acid is Met it is replaced by Leu and if the AA4 amino acid is Leu it is replaced by Met; when an AA5 amino acid in one of the sequences in Table 3 is replaced it is replaced by Glu, Asp or Gin, with the proviso that if the AA5 amino acid is Gin it is replaced by Glu or Asp, if the AA5 amino acid is Glu it is replaced by Gin or Asp, and if the AA5 amino acid is Asp it is replaced by Glu or Gin; and when an AAe amino acid in one of the sequences in Table 3 is replaced it is replaced by Glu, Asp or Gin, with the proviso that if the AAb amino acid is Gin it is replaced by Glu or Asp, if the AAb amino acid is Glu it is replaced by Gin or Asp, and if the AAe amino acid is Asp it is replaced by Glu or Gin.

The compound according to formula (I) can beselected those in Table 3 and, in particular can be selected from PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37 and PEP41 or from PEP1, PEP2, PEP3, PEP4, PEP21, PEP22, PEP23, and PEP24, and its stereoisomers, and/or its cosmetically or pharmaceutically acceptable salts. The compound can be PEP21, PEP22, PEP23, PEP24, PEP26, PEP27, PEP30, PEP31, PEP35, PEP36, PEP37 and PEP41. The compound can be PEP21 , PEP22, PEP23 or PEP24. The compound can be PEP21. The compound can be PEP22. The compound can be PEP23. The compound can be PEP24.

The cosmetically or pharmaceutically acceptable salts of the compounds of formula (I) are also found within the field of this invention. The term “cosmetically or pharmaceutically acceptable salt” means a salt recognized for its use in animals, for example, in mammals, and more specifically in human beings, and includes salts used to form base addition salts, either they are inorganic, for example and not restricted to, lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminium among others, or they are organic, for example and not restricted to, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine among others, or acid addition salts, either they are organic, for example and not restricted to, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate among others, or inorganic, for example and not restricted to, chloride, sulfate, borate or carbonate, among others. The nature of the salt is not critical, provided that it is cosmetically or pharmaceutically acceptable. The cosmetically or pharmaceutically acceptable salts of the compounds of the invention can be obtained by the conventional methods, well known in the prior art [Berge S.M. et al., "Pharmaceutical Salts", (1977), J. Pharm. Sci., 66, 1-19].

Synthesis of the compounds of formula (I), their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts can be carried out according to conventional methods, known in the prior art, such as solid phase peptide synthesis methods [Stewart J.M. and Young J.D., “Solid Phase Peptide Synthesis, 2nd edition”, (1984), Pierce Chemical Company, Rockford, Illinois; Bodanzsky M. and Bodanzsky A., “The practice of Peptide Synthesis”, (1994), Springer Verlag, Beriin; Lloyd-Williams P. et al., “Chemical Approaches to the Synthesis of Peptides and Proteins”, (1997), CRC, Boca Raton, PL, USA], synthesis in solution, enzymatic synthesis [Kullmann W. “Proteases as catalysts for enzymic syntheses of opioid peptides”, (1980), J.Biol.Chem., 255(17), 8234-8238] or any combination thereof. The compounds can also be obtained by fermentation of a bacterial strain, modified or unmodified by genetic engineering with the objective of producing the desired sequences, or by controlled hydrolysis of proteins with animal or plant origins, preferably plant, which results in free peptide fragments that contain the desired sequence.

For example, compounds of formula (I), their stereoisomers and mixtures thereof can be obtained as described in W02020031146A1. W02020031146A1 discloses the use of the peptides defined therein in the treatment and/or prevention of skin aging and wrinkle reduction. W02020031146A1 is silent regarding the use of these peptides for energizing the skin or preventing skin fatigue. The invention also extends to the use of the compounds of formula (I) in combination with a Botulinum toxin, Ac-Glu-Glu-Met-Gln-Arg-Arg-Nhk, or H-Tyr-D-Ala-Gly-Phe-Leu- OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH2 or combinations thereof. In one embodiment the invention extends to the use of the compounds of formula (I) in combination with H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-Nhfe.

Method of treatment

In another aspect, the invention provides a method of cosmetic, non-therapeutic treatment and/or care of the skin, of a subject comprising administering an effective amount of a compound of formula (I), a stereoisomer and/or cosmetically or pharmaceutically acceptable salt thereof or a composition comprising a cosmetically effective amount of a compound of formula (I), a stereoisomer and/or a cosmetically or pharmaceutically acceptable salt thereof, to the subject, wherein said cosmetic, non- therapeutic treatment and/or care is: the increase of energy metabolism and/or energy production in skin cells; the improvement and/or increase skin radiance; and/or the reduction and/or prevention of skin fatigue.

The invention also extends to the above-described methods of treatment and/or care of the skin wherein the compound of formula (I) is administered in combination with a Botulinum toxin, Ac-Glu-Glu-Met-Gln-Arg-Arg-Nhfe, H-Tyr-D-Ala-Gly-Phe-Leu-OH or H- Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-Nhh or combinations thereof.

The Botulinum toxin, Ac-Glu-Glu-Met-Gln-Ang-Arg-NH₂, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro-NH2 or combinations thereof and the compound of formula (I) can be administered simultaneously (at the same time) or administered one after the other. When the Botulinum toxin, Ac-Glu-Glu-Met-GIn-Arg- Arg-Nhfe, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg-Lys-Arg-Val-Pro- NH₂ or combinations thereof, and the compound or composition comprising an effective amount of a compound of formula (I) are administered at the same time, they can be administered as a separate dosage forms or as a part of a single composition. When the products are administered in separate dosage forms, the dosage forms can be in the same or different containers. The methods of treatment and/or care of the skin described herein can comprise the topical administration of the compound of formula (I) or a composition comprising a compound of formula (I).

For the above-described methods of the invention, topical ortransdermal application can be carried out by iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections, by needle-free injections by means of pressure, by microelectric patches, face masks or any combination thereof.

For the above-described methods of the invention, the frequency of application or administration can vary greatly, depending on the needs of each subject, with a recommendation of an application from once a month to ten times a day, preferably from once a week to four times a day, more preferably from three times a week to twice a day, even more preferably once a day. For example the frequency of the administration according to the method of treatment and/or care of the skin of a subject comprising administering a combination of the compound of formula (I), a stereoisomer and/or cosmetically or pharmaceutically acceptable salt thereof with a Botulinum toxin, Ac-Glu- Glu-Met-Gln-Arg-Arg-Nhfe, or H-Tyr-D-Ala-Gly-Phe-Leu-OH or H-Phe-Trp-Met-Lys-Arg- Lys-Arg-Val-Pro-NH₂ or combinations thereof, to the subject, can vary widely, depending on the need of each subject. In one embodiment, method of the invention comprises the administration of Botulinum toxin, followed by the administration of the compound of formula (I) or composition comprising a compound of formula (I). In a particular embodiment, after the administration of the Botulinum toxin, the compound of formula (I) or compositions comprising a compound of formula (I) are administered at least once a day for at least one week. More particularly, the compound of formula (I) or composition comprising a compound of formula (I) are administered at least once a day until the next administration of Botulinum toxin.

Cosmetic compositions comprising a compound according to formula (I), a stereoisomer and/or a cosmetically acceptable salt thereof, together with at least one cosmetically acceptable excipient or adjuvant can be prepared by conventional means known to persons skilled in the art [“Harry’s Cosmeticology”, Seventh edition, (1982), Wilkinson J.B., Moore R.J., ed. Longman House, Essex, GB].

The compounds of formula (I) have variable solubility in water, according to the nature of their amino acid sequence or any possible modifications in the N-terminal and/or C-terminal ends. Therefore, the compounds of formula (I) can be incorporated into the compositions by aqueous solution, and those which are not soluble in water can be solubilized in cosmetically or pharmaceutically acceptable conventional solvents such as and not restricted to, ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or any combination thereof.

The cosmetically effective amount of the compounds of formula (I) which should be administered, as well as their dosage, will depend on numerous factors, including age, state of the patient, the nature or severity of the condition, disorder or disease to be treated and/or cared for, the route and frequency of administration and of the particular nature of the compounds to be used.

The terms “cosmetically effective amount” and “pharmaceutically effective amount” are understood to mean a non-toxic but sufficient amount of the compound or compounds of the invention to provide the desired effect. The terms “pharmaceutically effective” and “therapeutically effective” are used interchangeably herein. The compounds of the invention are used in the cosmetic or pharmaceutical compositions of this invention at cosmetically or pharmaceutically effective concentrations to achieve the desired effect; for example in amounts with respect to the total weight of the composition of: from 0.00000001% (in weight) to 20% (in weight); from 0.000001% (in weight) to 15% (in weight), from 0.00001% (in weight) to 10% (in weight); or from 0.0001% (in weight) to 5% (in weight).

The compounds of formula (I), their stereoisomers, mixtures thereof and/or their cosmetic or pharmaceutically acceptable salts, can also be incorporated into cosmetic or pharmaceutical delivery systems and/or sustained release systems.

The term “delivery system” relates to a diluent, adjuvant, excipient or carrier with which the compound of the invention is administered. These cosmetic or pharmaceutical carriers can be liquids, such as water, oils or surfactants, including those of petroleum, animal, plant or synthetic origin, for example and not restricted to, peanut oil, soybean oil, mineral oil, sesame oil, castor oil, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltosides, fatty alcohols, nonoxynols, poloxamers, polyoxyethylenes, polyethylene glycols, dextrose, glycerol, digitonin and similar. A person skilled in the art knows the diluents, adjuvants or excipients which can be used in the different delivery systems in which the compound of the invention can be administered.

The term “sustained release” is used in a conventional sense relating to a delivery system of a compound which provides the gradual release of this compound during a period of time and preferably, although not necessarily, with relatively constant compound release levels over a period of time.

Examples of delivery or sustained release systems include, without restriction, liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, milliparticles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, surfactant- phospholipid mixed micelles, millispheres, microspheres and nanospheres, lipospheres, millicapsules, microcapsules and nanocapsules, as well as in microemulsions and nanoemulsions, which can be added to achieve a greater penetration of the active principle and/or improve its pharmacokinetic and pharmacodynamic properties. Preferred delivery or sustained release systems are liposomes, surfactant-phospholipid mixed micelles, microemulsions, more preferably water-in-oil microemulsions with an internal structure of reverse micelle and nanocapsules containing microemulsions.

In one embodiment, the cosmetic composition comprising a compound of formula (I) and a cosmetically or pharmaceutically acceptable carrier are selected from the group consisting of creams, emulsions, gels, liposomes, nanoparticles and ointments.

The sustained release systems can be prepared by methods known in the prior art, and the compositions which contain them can be administered, for example, by topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches and microelectric patches, or by systemic administration, for example and not restricted to, oral or parenteral route, including nasal, rectal or subcutaneous implantation or injection, or direct implantation or injection into a specific body part, and preferably should release a relatively constant quantity of the compounds of formula (I). The amount of compound contained in the sustained release system will depend, for example, on where the composition is to be administered, the kinetics and duration of the release of the compound of formula (I), as well as the nature of the condition, disorder and/or disease to be treated and/or cared for. The compounds of formula (I) can also be adsorbed on solid organic polymers or solid mineral supports such as and not restricted to, talc, bentonite, silica, starch or maltodextrin among others.

The compositions which contain the compounds of formula (I), their stereoisomers, mixtures thereof and/or their cosmetically or pharmaceutically acceptable salts can also be incorporated into fabrics, non-woven fabrics and medical devices which are in direct contact with the skin, thus releasing the compounds of the invention whether by biodegradation of the binding system to the fabric, non-woven fabric or medical device, or by friction between them and the body, due to bodily moisture, the skin’s pH or body temperature. Furthermore, the compounds of the invention can be incorporated into the fabrics and non-woven fabrics used to make garments that are in direct contact with the body.

Examples of fabrics, non-woven fabrics, garments, medical devices and means for immobilizing the compounds to them, among which are the delivery systems and/or the sustained release systems described above, can be found in literature and are known in the prior art [Schaab C.K. (1986) HAPPI May 1986; Nelson G., “Application of microencapsulation in textiles”, (2002), Int. J. Pharm., 242(1-2), 55-62; “Biofunctional Textiles and the Skin” (2006) Curr. Probl. Dermatol, v.33, Hipler U.C. and Eisner P., eds. S. KargerAG, Basel, Switzerland; Malcolm R.K. et at., “Controlled release of a model antibacterial drug from a novel self-lubricating silicone biomaterial”, (2004), J. Cont. Release, 97(2), 313-320], The preferred fabrics, non-woven fabrics, garments and medical devices are bandages, gauzes, t-shirts, socks, tights, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bedspreads, wipes, adhesive patches, nonadhesive patches, occlusive patches, microelectric patches and/or face masks.

The cosmetic compositions which contain the compounds of formula (I), their stereoisomers, mixtures thereof and/or their cosmetically acceptable salts, can be used in different types of compositions for topical or transdermal application which optionally include cosmetically or pharmaceutically acceptable excipients necessary for formulating the desired administration form.

The compositions for topical or transdermal application can be produced in any solid, liquid or semisolid formulation, such as and not restricted to, creams, multiple emulsions such as and not restricted to, oil and/or silicone in water emulsions, water-in-oil and/or silicone emulsions, water/oil/water or water/silicone/water type emulsions and oil/water/oil or silicone/water/silicone type emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balsams, foams, lotions, gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions, hydrogels, liniments, soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, pomades, powders, bars, pencils and sprays or aerosols (sprays), including leave-on and rinse-off formulations. These topical or transdermal application formulations can be incorporated using techniques known by the person skilled in the art into different types of solid accessories for example and not restricted to, bandages, gauzes, t-shirts, socks, tights, underwear, girdles, gloves, diapers, sanitary napkins, dressings, bedspreads, wipes, adhesive patches, nonadhesive patches, occlusive patches, microelectric patches or face masks, or they can be incorporated into different make-up products such as make-up foundation, such as fluid foundations and compact foundations, make-up removal lotions, make-up removal milks, under-eye concealers, eye shadows, lipsticks, lip protectors, lip gloss and powders among others.

The cosmetic compositions may include agents which increase the percutaneous absorption of the compounds of the invention, for example and not restricted to, dimethylsulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1- dodecylazacycloheptane-2-one), alcohol, urea, ethoxydiglycol, acetone, propylene glycol or polyethylene glycol, among others. Furthermore, the cosmetic compositions can be applied to local areas to be treated by means of iontophoresis, sonophoresis, electroporation, microelectric patches, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections or needle-free injections by means of pressure, such as injections by oxygen pressure, or any combination thereof, to achieve a greater penetration of the peptide of the invention. The application area will be determined by the nature of the condition, disorder and/or disease to be treated and/or cared for.

Among the cosmetically acceptable adjuvants contained in the cosmetic compositions described herein are additional ingredients commonly used in cosmetic or pharmaceutical compositions, for example and not restricted to anti-wrinkle agents, botox-like agents and/or anti-aging agents; (ii) firming agents, skin elasticity agents and/or restructuring agents; moisturizing agents; (iv) anti-photoaging agents, and/or blue-light protector agents; DNA protecting agents, DNA repair agents, and/or stem cell protecting agents; free radical scavengers and/or anti-glycation agents, detoxifying agents, antioxidant and/or anti-pollution agents; anti-perspirant agents; melanin synthesis stimulating or inhibiting agents; whitening or depigmenting agents; propigmenting agents; self-tanning agents; lipolytic agents or agents stimulating lipolysis, adipogenic agents, etc. Additional examples can be found in CTFA International Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008).

The cosmetic compositions described herein can comprise a compound of formula (I) and a cosmetically effective amount of an adjuvant selected from the group consisting of: (i) anti-wrinkle-agent, botox-like agent and/or anti-aging agent; (ii) firming agent, skin elasticity agent and/or restructuring agent; (iii) moisturizing agent; (iv) anti-photoaging agent, and/or blue-light protector agent; (v) DNA protecting agent, DNA repair agent, and/or stem cell protecting agent; (vi)free radical scavengers and/or anti-glycation agent, detoxifying agent, antioxidant and/or anti-pollution agents; and/or combinations thereof. Such adjuvants are known in the art and examples are given in W02019008452A1, for example.

The invention is illustrated by the following non-limiting examples.

EXAMPLES

EXAMPLE 1

In vitro study of ability of a compound to increase of the mitochondrial membrane potential in Human Dermal Fibroblasts using an immunofluorescent assay.

Mitochondria are intracellular organelles that play a vital role in cellular metabolism, including heme, fatty acid, and steroid synthesis; oxidative phosphorylation; Ca2+ homeostasis; and apoptosis. Mitochondria are enclosed within an outer and inner membrane. The inner membrane is more complex in structure, and contains the electron transport chain (ETC) complex and the complex for ATP synthesis through oxidative phosphorylation. This process consists of a series of redox reactions in which electrons are transferred from electron donors to electron acceptors. The energy released by electrons flowing through the ETC transports protons across the inner membrane, creating an electrochemical gradient. The electrochemical gradient consists of two parts, the electric potential and the proton gradient. This electrochemical gradient drives the synthesis of ATP. The mitochondrial membrane potential (MMP, Dyih) is generated by the electric potential across the inner mitochondrial membrane. Measuring the MMP is useful for evaluating mitochondrial function as it is a direct biomarker of adenosine triphosphate (ATP) synthesis, the main source of energy in the cell. For this reason, products with the ability to increase MMP can increase energy in cells and improve skin functions.

The main objective of this experiment was to evaluate the capacity of peptides to increase mitochondrial membrane potential in human dermal fibroblasts.

Human Dermal Fibroblasts from adult (HDFa, Life Technologies) are seeded at a density of 6,000 cells/well (3 wells per treatment) in 96-well plates. Cells are seeded in culture medium M106 with Low Serum Growth Supplement (Life Technologies) during 24 hours at 37°C in 5% C0₂ humidified air. Then, culture medium is removed and cells are treated with the peptide or peptide combinations set out above dissolved in Dulbecco’s Modified Eagle Medium (Life Technologies) supplemented with 10% (volume/volume) of fetal bovine serum (FBS, Cultek) for 16 hours at 37°C in 5% C0₂ humidified air. Non-treated cells incubated with medium alone are used as basal conditions. FCCP (carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone), which is an ionophore uncoupler of oxidative phosphorylation that inhibits the Dyiti, was used as negative control.

After 16 hours of treatment, cells were used to quantify mitochondria membrane potential by using JC-1 mitochondrial membrane potential assay kit (Abeam) according to the manufacturer’s protocol. Briefly, cells are incubated with a JC-1 working solution prepared with Supplemented Dilution Buffer in the presence of the treatment with the peptide (each treatment is always present during the assay) at 37^°C in 5% C0₂ for 30 minutes. The JC-1 dye fluoresces red or green, respectively, when it aggregates in healthy mitochondria with high membrane potentials (hyperpolarization; energized cells) or exists as a monomer in mitochondria with diminished membrane potential (depolarization; non-energized cells).

Cells are imaged and mitochondrial membrane potential is measured using Operetta^® High Content Imaging System (PerkinElmer, Inc). In energized cells, red aggregates appear, and the dye emits at 560-630 nm when excited at 520-550 nm. In depolarized cells, the dye emits at 500-550 nm when excited at 460-490 nm. Cell number is quantified by using Hoechst 33342 (ThermoFisher Scientific) staining, a cell- permeant nuclear counterstain that emits blue fluorescence at 460nm when bound to dsDNA and is excited at 350nm. For each image, intensity fluorescence from energized and depolarized cells is quantified and normalized against the number of nuclei. The mean of the percentage of mitochondrial membrane potential after the treatment of cells with peptide or peptide combinations relative to basal conditions is summarized in Table 4. These values represent the values for at least three independent assays.

Relative MMP

T reatment Dose Tested

(MEAN ± SEM)

Basal CTR 100.00 ± 3.23 FCCP 10 mM 12.95 ± 0.23 PEP23 0.2 mg/ml 105.9 ± 5.81 PEP23 0.5 mg/ml 135.50 ± 13.18

H-Phe-T rp-Met-Lys-Arg-

0.25 mg/ml 111.10 ± 3.71 Lys-Arg-Val-Pro-Nhfe

H-Phe-T rp-Met-Lys-Arg-

0.5 mg/ml 139.00 ± 8.26 Lys-Arg-Val-Pro-NH₂

Table 4

PEP23 was able to increase the mitochondrial potential of HDFa cells, which demonstrates the capacity of the peptide to increase the cell energy metabolism. Advantageously, PEP23 is relatively small (6 amino acids) compared with H-Phe-Trp- Met-Lys-Arg-Lys-Arg-Val-Pro-NH2 (9 amino acids) and therefore can be prepared more efficiently. EXAMPLE 2

Cosmetic composition for in vivo testing

A cosmetic copostion was prepared by the following process:

- Dissolving phase A in an adequate vessel and adding Carbopol® Ultrez 21 Polymer (from the Lubrizol Corporation) (Phase A1). complete dispersion.

- Mixing phase A2 until complete dispersion.

- Mixing phase B in a separate vessel, then additing to phase A while mixing with a turbine.

- Adding phase C while mixing with overhead stirrer with a dispersion blade. - Adding phase D to adjust pH to 6-6.5. PHASE INGREDIENTS % A Water (Aqua) q.s.p. 100

Propanediol 10.00 Potassium Sorbate 0.10 Disodium EDTA 0.20

A1 Carbopol^®Ultrez 21 polymer 0.65

A2 Xanthan Gum 0.20

B Schercemol™ 1818 ester 2.00

Phenoxyethanol 0.35 C PEP23 2.00

D Sodium Hydroxide (20% w/w)

Table 5

EXAMPLE 3 Radiance and anti-fatigue effect

Forty (40) healthy female volunteers were enrolled under the supervision of a board- certified dermatologist from a panel of healthy subjects, in accordance with the following inclusion and non-inclusion criteria.

Inclusion criteria:

- Aged between 30 and 60 years old with clinical signs of skin aging such as fine lines or slight/moderate wrinkledness in the crow’s feet area.

- Subjects who have not been recently (at least 3 weeks) in any other similar study and/or using any similar product.

- Willingness to not use during all the study period topic products with similar effect to that one of the products to be tested.

- Willingness not to change the usual daily routine.

- Subjects informed of the trial procedures who have signed an informed consent form.

Exclusion criteria:

- Subjects who do not fit the inclusion criteria.

- Subjects that have shown allergies to cosmetic products, toiletries, sunscreens and/or topical drugs.

- Subjects with skin disorders on the test area. - Subjects under pharmacological treatment (both locally or systemically) that may interfere with the test execution.

Positive anamnesis for atopy (if this condition interferes with the test execution). The study was carried out for 28 days. Subjects apply the composition described in Example 2 (Active Cream) on one side of the face (left or right) and a Placebo Cream having the same composition except the peptide of the invention on the other side of the face. Active and Placebo Cream are applied for 28 days twice a day (morning and evening).

The skin radiance (or skin brightness), is the ability of the skin to reflect the light and it is measured using the gloss parameter (taken using the spectrophotometer/colorimeter CM-700D (Konica-Minolta). The gloss value is used in the management of the brilliance of the color.

Fatigue effect (or tiring effect) was determined by a Cutometer® MPA 580 (Courage+ Khazaka electronic GmbH) by determining the R9 value, wherein smaller values represent smaller tiring effect.

Table 6

The results show that the Active Cream significantly increases skin radiance compared to the Placebo Cream. The Active Cream significantly reduced skin tiredess which can be correlated with a reduction of skin fatigue.

Claims

CLAIMS:

1 . Use of a compound of formula (I)

R1- AA1-AA2-AA3-AA4-AA5-AA6-R2 (I), a stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AAi is Arg or Lys;

AA₂ is Arg or Lys;

AA3 is Gin, Glu, Asn or Asp;

AA4 is Met or Leu;

AA₅ is Glu, Asp or Gin;

AA_e is Glu, Asp or Gin;

Ri is selected from the group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl, aralkyl and R5-CO-, wherein R5 is selected from the group consisting of H, a non- cyclic aliphatic group, alicyclyl, aryl, aralkyl, heterocyclyl and heteroarylalkyl;

R2 is selected from the group consisting of-NR3R4, -OR3.-SR3, wherein R3 and R4 are independently selected from a group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and Ri and R2 are not amino acids, for the cosmetic non-therapeutic treatment and/or care of the skin, wherein said cosmetic non-therapeutic treatment and/or care is the increase of energy metabolism and/or energy production in skin cells.

2. Use of a compound of formula (I)

AAi is Arg, or Lys;

AA2 is Arg or Lys; AA₃ is Gin, Glu, Asn or Asp;

AA4 is Met or Leu;

AA₅ is Glu, Asp or Gin;

AAb is Glu, Asp or Gin;

R₂ is selected from the group consisting of-NR₃R₄, -OR₃.-SR₃, wherein R₃ and R₄ are independently selected from a group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and Ri and R₂ are not amino acids, for the cosmetic non-therapeutic treatment and/or care of the skin, wherein said cosmetic non-therapeutic treatment and/or care is improving and/or increasing skin radiance.

3. Use of a compound of formula (I)

AAi is Arg, or Lys;

AA₂ is Arg or Lys;

AA3 is Gin, Glu, Asn or Asp;

AA4 is Met or Leu;

AA5 is Glu, Asp or Gin;

AAb is Glu, Asp or Gin;

R2 is selected from the group consisting of-NR₃R4, -OR₃.-SR₃, wherein R₃ and R4 are independently selected from a group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and Ri and R₂ are not amino acids, for the cosmetic, non-therapeutic treatment and/or care of the skin, wherein said cosmetic, non-therapeutic treatment and/or care is the reduction and/or prevention of skin fatigue.

4. Method of cosmetic, non-therapeutic treatment and/or care of the skin of a subject comprising administering a cosmetically effective amount of a compound of formula (I) R1- AA1-AA2-AA3-AA4-AA5-AA6-R2 (I), a stereoisomer and/or cosmetically acceptable salt thereof, wherein:

AAi is Arg, or Lys;

AA2 is Arg or Lys; AA₃ is Gin, Glu, Asn or Asp;

AA₄ is Met or Leu;

AA₅ is Glu, Asp or Gin;

AAb is Glu, Asp or Gin;

R2 is selected from the group consisting of-NR3R4, -OR3.-SR3, wherein R3 and R4 are independently selected from a group consisting of H, a polymer derived from polyethylene glycol, a non-cyclic aliphatic group, alicyclyl, heterocyclyl, heteroarylalkyl, aryl and aralkyl; and Ri and R2 are not amino acids, to the subject, wherein said cosmetic non-therapeutic treatment and/or care is the increase of energy metabolism and/or energy production in skin cells; improving and/or increasing skin radiance; and/or the reduction and/or prevention of skin fatigue.

5. Use according to any of claims 1 to 3, or method according to claim 4 wherein AA3 is Gin or Asp.

6. Use according to any of claims 1 to 3 or 5, or method according to claim 4 or 5, wherein AA5 is selected from the group consisting of Glu and Asp; and AAe is selected from the group consisting of Glu or Gin.

7. Use according to any of claims 1 to 3, 5 or 6, or method according to any of claims

4 to 6, wherein AAi is Arg and/or AA2 is Arg.

8. Use according to any of claims 1 to 3, 5 or 7, or method according to any of claims 4 to 7, wherein AA3 is Gin, AA4 is Met, AA5 is Glu and/or AAb is Glu.

9. Use according to any of claims 1 to 3 or 5 to 8, or method according to any of claims 4 to 8, wherein at least one of AAi, AA₂, AA3, AA4, AA5 and AAe is a D-amino acid.

10. Use according to any of claims 1 to 3 or 5 to 9, or method according to any of claims 4 to 9, wherein 1 , 2 or 3 of AA3, AA4 and AAs is a D-amino acid and the remaining of AAi to AAb are L-amino acids.

11 . Use according to claim 10, or method according to claim 10, wherein the compound has a formula of:

Ri-L-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-R₂ (II);

Ri -L-Arg-L-Arg -L-GI n-D-M et-L-GI u-L-G I u -R₂ (III);

Ri-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-R₂ (IV).

12. Use according to any of claims 1 to 3 or 5 to 11 , or method according to any of claims 4 to 11, wherein Ri is selected from the group consisting of H and R5-CO-, wherein R5 is selected from the group consisting of C1-C18 alkyl, C₂-C_¾ alkenyl, C3-C₂4 cycloalkyl; and R₂ is -NR3R4 or -OR3 wherein l¾ and l¾ are independently selected from the group consisting of H and C1-C16 alkyl.

13. Use according to claim 12, or method according to claim 12, wherein Ri is selected from the group consisting of H, acetyl, or palmitol, lauroyl or myristyl; and R_å is -NR3R4 or -OR3 wherein R3 and R4 are independently selected from the group consisting of H and C1-C16 alkyl.

14. Use according to claim 13, or method according to claim 13, wherein Ri is selected from the group consisting of H, acetyl, or palmitol; and R₂ is -NH₂ or -OH wherein R3 is H and R4 is H and, preferably Ri is acetyl and R₂ is NH₂.

15. Use according to any of claims 1 to 3 or 5 to 14, or method according to any of claims 4 to 14, wherein the compound is

Ac-Arg-L-Arg-D-Gln-L-Met-L-Glu-L-Glu-NH₂(PEP22); Ac-L-Arg-L-Arg-L-Gln-D-Met-L-Glu-L-Glu-NH₂(PEP23); Ac-L-Arg-L-Arg-D-Gln-D-Met-L-Glu-L-Glu-NH₂ (PEP24).