Compositions and uses of non-cyclic peptides

Abstract

The present invention relates to non-cyclic peptides having advantageous applications in non-therapeutic and therapeutic indications. Such peptides are particularly effective as growth factors, as they activate TGF-β pathway, thus making such non-cyclic peptides efficient to achieve diverse skin cosmetic and therapeutic benefits.

Description

DescriptionTitle of Invention: Uses of non-cyclic peptidesTechnical Field

[0001] The present invention relates to non-cyclic peptides having advantageous applications in non-therapeutic and therapeutic indications. Such peptides are particularly effective as growth factors, as they activate skin cells, in particular fibroblasts and / or keratinocytes, in the case of fibroblasts preferably by activating the TGF-[3 pathway, thus making such non-cyclic peptides efficient to achieve diverse skin cosmetic and therapeutic benefits.Background Art

[0002] Transforming growth factor [3 (TGF-[3) is a cytokine growth factor involved in cell proliferation, differentiation and apoptosis and controls many physiological and pathological processes. The medical application of TGF-[3 have been extensively studied. A review of such application is provided in Clinical Medicine & Research Volume 1 , Number 1 : 13-20 (2003).

[0003] Among other effects, TGF-[3 is one of the key activators of fibroblasts. Fibroblasts play an important role in the formation of connective tissues, including collagen formation, tissue repair and wound healing.

[0004] There is a need to find compounds that can act as a replacement for TGF-[3, particularly for skin care applications. Indeed, TGF-[3 has a significant drawback with respect to such applications, due to its high molecular weight, which limits its ability to penetrate the tightly packed stratum corneum. This is also the case of most growth factors and cytokines. There is therefore a need to find compounds that can act as growth factors, preferably that are able to activate TGF-[3 pathway, while being capable of penetrating the stratum corneum.

[0005] Defensins are members of a large family of small cationic peptides. Such peptides have mainly been described as having antimicrobial activity and as being involved in host immunity, playing a role as host defense peptides in vertebrates, invertebrates, plants, and molds. Based on disulfide topology, mammalian defensins are classified into three subfamilies, a, |3, and 9-defensins.In humans, only a and [3-defensins are expressed. 0-Defensins are cyclic defensin stabilized by three parallel disulfide bonds that have been found only in rhesus macaques. RNA transcripts homologous to the 0-defensin gene exist in humans but are not translated due to the presence of a premature stop codon.

[0006] Activity of 0-defensins has been investigated in the prior art. For example, W02000 / 68265A1 discloses 0-defensin peptides and their antimicrobial activity. US2004 / 014669A1 also relates to antimicrobial activity of defensin. Several different variants of defensins are tested, among which non-cyclic peptides. Non- cyclic peptides proved less efficient than cyclic ones.

[0007] The activity of 0-defensins has also been assessed in Conibear et al., The Journal of Biological Chemistry vol. 288, No. 15, pp. 10830-10840, 2013, wherein non-cyclic 0-defensin peptides were shown to lose their antimicrobial activity, compared to cyclic 0-defensin peptides, suggesting that 0-defensin's activity was subject to its cyclic structure.

[0008] In WO2015 / 195677A1 , defensins in general have also been disclosed in topical cosmetic formulations in sub-antimicrobially effective concentrations and proved effective in recruiting LGR6+ stem cells from hair follicles to the interfoll icu lar space. Such effect is disclosed as being beneficial against wrinkle depth, wrinkle length, wrinkle width, pore size, irregularity in texture of a skin surface, oiliness, brown spots, and red spots in non-injured skin, thus reducing apparent age. 0-Defensins are listed as suitable defensins but examples only involve a- and [3-defensins. Plast Reconstr Surg. 2013 Nov; 132(5): 1159-1171 , which is the scientific paper disclosing the work reported in WO2015 / 195677A1 , even more clearly shows that the above-mentioned activity is rather limited and not general to all defensins.

[0009] In WO2017 / 105413A1 , defensins in general have also been disclosed in topical cosmetic formulations to reduce or eliminate the appearance of melasma. Again, 0-defensins are listed as suitable defensins but examples only involve a- and [3-defensins.

[0010] Furthermore, CN116270971 A teaches that 0-defensins are effective for improving wound healing.

[0011] Despite what is known in the prior art, there is still a need to identify further actives molecules that provide benefits on the appearance and the function of the skin, and that would have beneficial effects on skin cells, such as fibroblast and / or keratinocytes. It would be particularly desirable to provide further active molecules that promote activation, proliferation, growth and / or migration of skin cells, such as fibroblasts and / or keratinocytes. It would be even preferable to identify compounds having improved efficacy in the activation of fibroblasts and / or keratinocytes, compared to the prior art compounds.

[0012] Furthermore, it would be advantageous to provide active molecules achieving the above-mentioned benefits while being deprived from broad antimicrobial activity. Indeed, the long-term use of broad-spectrum antimicrobial substances, for example in cosmetic applications, contributes to the undesirable development of antimicrobial resistance.Summary of Invention

[0013] In a first aspect, the present invention provides a cosmetic composition comprising at least one non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23, or to a variant or derivative thereof.

[0014] In a second aspect, the present invention provides a pharmaceutical composition comprising at least one non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23, or to a variant or derivative thereof.

[0015] In a third aspect, the present invention provides for the non-therapeutic use of a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof; or of b. a cosmetic composition of the invention for the preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject.

[0016] In a fourth aspect, the present invention provides for the non-therapeutic use of a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23or to a variant or derivative thereof; or of b. a cosmetic composition of the invention for rejuvenating the skin, for preventing and / or slowing down skin ageing and / or for strengthening the skin of a subject.

[0017] In a fifth aspect, the present invention provides for the non-therapeutic use of a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23or to a variant or derivative thereof; or of b. a cosmetic composition of the invention for preventing, reducing and / or non-therapeutically treating the intrinsic and extrinsic signs of skin aging.

[0018] In a sixth aspect, the present invention provides for a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:1 to 13, 15 or 20 to 23, to a variant or to a derivative thereof for use in therapy, in other words for use as a medicament.

[0019] In a seventh aspect, the present invention provides for a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:1 to 13, 15 or 20 to 23, to a variant or to a derivative thereof; or b. a pharmaceutical composition of the invention for use in promoting healing in soft and hard tissues and for use as an immunosuppressive agent in a subject in need thereof.

[0020] In an eighth aspect, the present invention provides a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:3 to 7 or 20 to 23, a variant or a derivative thereof.Brief Description of Drawings

[0021] [Fig.1 ]: Concentration of Procollagen 1 after 48 hours incubation with the non- cyclic peptide of SEQ ID NO: 13 (labelled as NP-711 ) and with the non-cyclic peptide of SEQ ID NO:9 (labelled as NP-716) at 3 pM. Results are expressed in ng / mL and compared to untreated control and reference TGF0 (10ng / mL). Results are shown ± SD

[0022] [Fig. 2]: Dose effect for the non-cyclic peptide of SEQ ID NO:9 (labelled as XEP-716). Results are expressed as the concentration of Procollagen 1 (pg / mL) as a function of peptide concentration (pM). Results are shown ± SEM.

[0023] [Fig. 3]: Dose effect for the non-cyclic peptide of SEQ ID NO:9 (labelled as XEP-716) and of its cyclic analogue RTD-2. Results are expressed as the concentration of Procollagen 1 (ng / mL) as a function of peptide concentration (pM) and compared to untreated control and reference TGF0 (10 ng / mL). Results are shown ± SEM.

[0024] [Fig. 4]: Dose effect for the non-cyclic peptide of SEQ ID NO:9 (labelled as XEP-716) and of its cyclic analogue RTD-2. Results are expressed as the concentration of Collagen (pg / section) as a function of peptide concentration (pM) and compared to untreated control and reference TGF0 (10 ng / mL). Results are shown ± SEM.

[0025] [Fig. 5]: Concentration of hyaluronic acid after 72 hours incubation with the non-cyclic peptide of SEQ ID NO:9 (labelled as 716) and its cyclic analogue (labelled as RTD-2) at 5 pM. Results are expressed in ng / mL and compared to untreated control and reference TGF0 (10 ng / mL). Results are shown ± SEM.

[0026] [Fig. 6]: Fold-change in expression for the 9368 genes that are up- or down- regulated by TGFp or the non-cyclic peptide of SEQ ID NO: 9 (labelled as XEP- 716).

[0027] [Fig. 7]: Cumulative percentage of applied quantity recovered at each time point in the receptor fluid compartment of the permeability assays of the non- cyclic peptide of SEQ ID NO:9 on reconstructed epidermis.

[0028] [Fig. 8]: Clinical grading of wrinkle severity after repeated application of a cream comprising the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 9.

[0029] [Fig. 9]: Assessment of skin firmness after repeated application of a cream comprising the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 10.

[0030] [Fig. 10]: Assessment of skin homogeneity after repeated application of a cream comprising the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 11 .

[0031] [Fig. 11]: Assessment of skin firmness after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 12.

[0032] [Fig. 12]: Assessment of skin firmness after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 12.

[0033] [Fig. 13]: Assessment of skin elasticity after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 12.

[0034] [Fig. 14]: Assessment of skin elasticity after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 12.

[0035] [Fig. 15]: Assessment of dermis density after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 13.

[0036] [Fig. 16]: Assessment of dermis density after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 13.

[0037] [Fig. 17]: Assessment of dermis thickness after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 13.

[0038] [Fig. 18]: Assessment of dermis density after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 13.

[0039] [Fig. 19]: Assessment of Dermo-Epidermal Junction (DEJ) after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0040] [Fig. 20]: Assessment of Dermo-Epidermal Junction (DEJ) after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0041] [Fig. 21]: Assessment of edged papillae density after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0042] [Fig. 22]: Assessment of edged papillae density after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0043] [Fig. 23]: Assessment of young collagen fiber perimeter after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0044] [Fig. 24]: Assessment of young collagen fiber perimeter after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0045] [Fig. 25]: Assessment of total collagen fiber perimeter after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0046] [Fig. 26]: Assessment of total collagen fiber perimeter after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 14.

[0047] [Fig. 27]: Assessment of stratum corneum thickness after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 15.

[0048] [Fig. 28]: Assessment of stratum corneum thickness after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 15.

[0049] [Fig. 29]: Assessment of skin lipidic index after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 16.

[0050] [Fig. 30]: Assessment of skin lipidic index after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 16.

[0051] [Fig. 31]: Assessment of red spots count after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 17.

[0052] [Fig. 32]: Assessment of red spots count after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 17.

[0053] [Fig. 33]: Assessment of red spots area after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 17.

[0054] [Fig. 34]: Assessment of brown spots count after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 18.

[0055] [Fig. 35]: Assessment of brown spots count after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 18.

[0056] [Fig. 36]: Assessment of brown spots area after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 18.

[0057] [Fig. 37]: Assessment of brown spots area after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 18.

[0058] [Fig. 38]: Assessment of UV spots count after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 18.

[0059] [Fig. 39]: Assessment of UV spots count after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 18.

[0060] [Fig. 40]: Assessment of visible spots count after repeated application of a cream comprising 2.5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 19.

[0061] [Fig. 41]: Assessment of visible spots count after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 19.

[0062] [Fig. 42]: Assessment of visible spots count after repeated application of a cream comprising 5 % of the non-cyclic peptide of SEQ ID NO: 9 compared to the cream vehicle alone, as assessed in Example 19.Detailed DescriptionGeneral definition of non-cyclic peptides

[0063] The present inventors have surprisingly identified that non-cyclic peptides such as described herein were effective in activating TGF[3 pathway and therefore to act as growth factors, as will be demonstrated in the examples below. Such non-cyclic peptides are advantageous over growth factors such as TGF[3 in that their lower molecular weight enables penetration of the peptide through the skin barrier and in turn enables interaction with fibroblasts and keratinocytes. Non-cyclic peptides proved efficient in promoting activation, proliferation, growth and / or migration of fibroblasts and / or keratinocytes, particularly of fibroblasts, thus generating key cosmetic and therapeutic benefits on the skin, such as described below.

[0064] The terms “Non-cyclic peptide(s)” as used herein refers to a peptide which has an N-terminal and a C-terminal amino acid that are each only bound to one other amino acid via a peptide bond. Thus, this most common form of a non- cyclic peptide has a free N-terminus and a free C-terminus. A non-cyclic peptide is not closed peptide rings wherein each amino acid of is bound to its two neighboring amino acids by a peptide bond. Non-cyclic peptides may comprise S- S bridges. In contrast to 9-defensins which require a cyclic structure (Conibear et al., ) for their anti-microbial activity, it was surprisingly found that the fibroblast and / or keratinocyte activation, in the case of fibroblasts, preferably the TGF[3 pathway activation, as described herein, is exerted by non-cyclic peptides.

[0065] The disclosure of a “non-cyclic peptide” in any aspect or embodiment of the disclosure herein shall likewise disclose a variant or a derivative of the respective non-cyclic peptide to the extend such variant or derivative is still non-cyclic.

[0066] The non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence having up to 18 amino acids, preferably having 18 amino acids, and comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:1 to 13, 15 or 20 to 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof.

[0067] The non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acidsequences SEQ ID N0:1 to 13, 15 or 20 to 23, a variant or a derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence having up to 18 amino acids, preferably having 18 amino acids, and comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:1 to 13, 15 or 20 to 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO: 1 to 13 or 15 to 20 to 23, or to a variant or a derivative thereof.

[0068] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:1 to 10, 13, 15 or 20 to 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 1 to 10, 13, 15 or 20 to 23 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence having up to 18 amino acids, preferably having 18 amino acids, and comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:1 to 10, 13, 15 or 20 to 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 1 to 10, 13, 15 or 20 to 23 to a variant or derivative thereof.

[0069] The non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO: 1 to 10, 13, 15 or 20 to 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:1 to 10, 13, 15 or 20 to 23 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO: 1 to 10, 13, 15 or 20 to 23, a variant or a derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence having up to 18 amino acids, preferably having 18 amino acids, and comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO: 1 to 10, 13, 15 or 20 to 23 or to a variant or derivative thereof,preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:1 to 10, 13, 15 or 20 to 23, or to a variant or a derivative thereof.

[0070] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:2 to 13, 15, 20,22 or 23 or a to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 2 to 13, 15, 20, 22 or 23 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:2 to 13, 15, 20, 22 or23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 2 to 13, 15, 20, 22 or 23 or to a variant or derivative thereof.

[0071] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:2 to 13, 15, 20, 22 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO: 2 to 13, 15, 20, 22 or 23 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:2 to 13, 15, 20, 22 or 23 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:2 to 13, 15, 20, 22 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO: 2 to 13, 15, 20, 22 or 23 or to a variant or derivative thereof.

[0072] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:2 to 10, 13, 15,20, 22 or 23 or a to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or to a variant or derivative thereof.

[0073] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:2 to 10, 13, 15, 20, 22 or 23 or to a variant or derivative thereof.

[0074] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4 to 13, 15 or 20 or a to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 4 to 13, 15 or 20 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4 to 13, 15 or 20 or to a variant orderivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO: 4 to 13, 15 or 20 or to a variant or derivative thereof.

[0075] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:4 to 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO: 4 to 13, 15 or 20 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:4 to 13, 15 or 20 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4 to 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO: 4 to 13, 15 or 20 or to a variant or derivative thereof.

[0076] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or a to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or to a variant or derivative thereof.

[0077] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:4 to 10, 13, 15 or 20 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4 to 10, 13, 15 or 20 or to a variant or derivative thereof.

[0078] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or a to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or to a variant or derivative thereof.

[0079] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:4, 6, 9 to 13, 15 or 20 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or to a variant orderivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 6, 9 to 13, 15 or 20 or to a variant or derivative thereof.

[0080] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or a to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or to a variant or derivative thereof.

[0081] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 6, 9, 10, 13, 15 or 20 or to a variant or derivative thereof.

[0082] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 9 or 11 to 13 ora to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 9 or 11 to 13 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 9 or 11 to 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 9 or 11 to 13 or to a variant or derivative thereof.

[0083] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 9 or 11 to 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 9 or 11 to 13 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:4, 9 or 11 to 13 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 9 or 11 to 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 9 or 11 to 13 or to a variant or derivative thereof.

[0084] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 9, 11 or 13 or a to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 9, 11 or 13 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 9, 11 or 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %,92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4, 9, 11 or 13 or to a variant or derivative thereof.

[0085] In a preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 9, 11 or 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 9, 11 or 13 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:4, 9, 11 or 13 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4, 9, 11 or 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4, 9, 11 or 13 or to a variant or derivative thereof.

[0086] In a more preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:2 and 8 to 13, or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof.

[0087] In an even more preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as apeptide having an amino acid sequence comprising any one of the amino acid sequences SEQ ID NO:2 and 8 to 13 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof.

[0088] In an even more preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:9 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to SEQ ID NO:9 or to a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:9 or a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to SEQ ID NO:9 or to a variant or derivative thereof.

[0089] In a most preferred aspect, the non-cyclic peptide used in the invention is defined as a peptide having a sequence comprising an amino acid sequence at least 85% identical to SEQ ID NO:9 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to SEQ ID NO:9 or to a variant or derivative thereof. Preferably the non-cyclic peptide is defined as a peptide having an amino acid sequence comprising the amino acid sequence SEQ ID NO:9 or a variant or a derivative thereof. In a preferred aspect, the non-cyclic peptide is defined as a peptide having a sequence consisting of an amino acid sequence at least 85% identical to SEQ ID NO:9 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to SEQ ID NO:9 or to a variant or derivative thereof.

[0090] The terms “homology” or "homologous" as used herein refer to the percentage of homology between two polypeptide moieties. Homology can be determined by readily available computer programs.

[0091] In general, "percent identity" of two amino acid sequences can be determined using the algorithm of Karlin and Altschul Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, modified as in Karlin and Altschul Proc. Natl. Acad. Sci. USA 90:5873-77, 1993. Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. J. Mol. Biol. 215:403-10, 1990. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules of interest. Where gaps exist between two sequences, Gapped BLAST can be utilized as described in Altschul et ah, Nucleic Acids Res. 25(17):3389-3402, 1997. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs {e.g., XBLAST and NBLAST) can be used.

[0092] The term "derivative" of peptide, as used herein, refers to a peptide comprising an amino acid which has been derivatised by chemical modification, such as for example deamidation, alkylation, especially N-alkylation, acylation, carbamylation, prenylation, carboxylation, hydroxylation, iodination, phosphorylation, sulfation, glycation, carbonylation, nitration, ubiquitination, amidation.

[0093] The term "variant" of a peptide, as used herein, refers to a peptide comprising at least one amino acid substitution, insertion and / or deletion, provided that such peptide retains its activity as disclosed herein in any embodiment of the invention.

[0094] The term "similar" as used herein refers to the peptide variants having one or more conservative substitution(s). A conservative substitution is a substitution wherein the substituted amino acid has been replaced by another amino acid that does not to substantially change the function of the peptide. More particularly, a conservative substitution (also called a conservative mutation or a conservative replacement) is an amino acid replacement in a protein that changes a given amino acid to a different amino acid with similar biochemical properties (e.g. charge, hydrophobicity and size). Conservative substitutions are well-known to the person skilled in the art and are for example defined in commonly useddatabases and in the reference Molecular Biology and Evolution, Volume 19, Issue 7, July 2002, Pages 1022-1025.

[0095] In a particular aspect of the invention, the non-cyclic peptide is substantially devoid of antimicrobial activity, irrespective of its concentration. A “substantially devoid of antimicrobial activity” according to the present invention is an antimicrobial activity against E. coli or S. aureus in an assay as described in Conibear et al (2013) which is at most 15%, at most 10%, at most 5%, at most, or 2,5% of the corresponding circular peptide. Alternatively, the non-cyclic peptide is used at concentrations below the threshold of the antimicrobial activity.

[0096] In another particular aspect, the non-cyclic peptide binds to TGF[3-Receptor 1 (TGFb-R1 or T[3RI) with a half-maximal receptor binding concentration of from about 5 ng / ml to about 100 ng / ml, preferably from about 20 ng / ml to about 60 ng / ml, more preferably from about 25 ng / ml to about 35 ng / ml and / or to TGF[3- Receptor 2 (TGFb-R2 or T|3RI I) with a half-maximal receptor binding concentration of from about 200 ng / ml to about 800 ng / ml, preferably from about 400 ng / ml to about 700 ng / ml, more preferably from about 550 ng / ml to about 650 ng / ml. Preferably, the half-maximal receptor binding concentration of the peptide is as measured by the method consisting of immobilizing the peptide and increasing the receptor concentration (ng / ml) in contact with the peptide until the concentration is sufficient to achieve 50% association of the receptors with the peptide. The half-maximal receptor binding concentration is the concentration of the receptor wherein 50% association is achieved. A suitable method such as described herein for measuring the half-maximal receptor binding concentration is provided in details in Example 2 below.Non-cyclic peptide as a product

[0097] A non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof, has not been disclosed in the prior art. Such non-cyclic peptide is therefore an object of the invention per se. Preferably the non-cyclic peptide is a peptide having anamino acid sequence comprising any one of amino acid sequences SEQ ID NO:3 to 7, 20 or 23 or a variant or derivative thereof. In a preferred aspect, the non- cyclic peptide is a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof. In an even more preferred aspect, the non-cyclic peptide is a peptide consisting of any one of the amino acid sequences SEQ ID NO: 3 to 7, 20 or 23 or a variant or derivative thereof.

[0098] In a preferred aspect, the non-cyclic peptide has a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:3 to 7 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:3 to 7 or to a variant or derivative thereof, has not been disclosed in the prior art. Such non-cyclic peptide is therefore an object of the invention per se. Preferably the non-cyclic peptide is a peptide having an amino acid sequence comprising any one of amino acid sequences SEQ ID NO:3 to 7 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:3 to 7 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:3 to 7 or to a variant or derivative thereof. In an even more preferred aspect, the non-cyclic peptide is a peptide consisting of any one of the amino acid sequences SEQ ID NO: 3 to 7 or a variant or derivative thereof.

[0099] In a preferred aspect, the non-cyclic peptide has a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:4 or 6 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4 or 6 or to a variant or derivative thereof, has not been disclosed in the prior art. Such non-cyclic peptide is therefore an object of the invention per se. Preferably the non-cyclic peptide is a peptide having an amino acid sequence comprising any one of amino acid sequences SEQ ID NO:4or 6 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4 or 6 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4 or 6 or to a variant or derivative thereof. In an even more preferred aspect, the non-cyclic peptide is a peptide consisting of any one of the amino acid sequences SEQ ID NO:4 or 6 or a variant or derivative thereof.

[0100] In a preferred aspect, the non-cyclic peptide has a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:4 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:4 or to a variant or derivative thereof, has not been disclosed in the prior art. Such non-cyclic peptide is therefore an object of the invention per se. Preferably the non-cyclic peptide is a peptide having an amino acid sequence comprising any one of amino acid sequences SEQ ID NO:4 or a variant or derivative thereof. In a preferred aspect, the non-cyclic peptide is a peptide having a sequence consisting of an amino acid sequence at least 85% identical to any one of SEQ ID NO:4 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% identical to any one of SEQ ID NO:4 or to a variant or derivative thereof. In an even more preferred aspect, the non-cyclic peptide is a peptide consisting of any one of the amino acid sequences SEQ ID NO:4 or a variant or derivative thereof.Cosmetic composition

[0101] The invention relates to a cosmetic composition comprising at least one non- cyclic peptide such as described above. The cosmetic composition is preferably a topical cosmetic composition, i.e. a composition suitable for application to the skin.

[0102] The cosmetic composition can further comprise any cosmetically acceptable carrier, diluent and / or adjuvant. Such carriers, diluents and adjuvants are well- known to the person skilled in the art.

[0103] In particular embodiments, the compositions of the present invention may comprise a wide range of additional ingredients. The 2010 International Cosmetic Ingredient Dictionary and Handbook, 13th edition and the 2009 Cosmetic Bench Reference — Directory of Cosmetic Ingredients (published by Cosmetics & Toiletries; ISBN-13: 978-1-932633-43-6) describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care and dermatology industry, which are available for use in the present invention. Exemplary functional classes include (see 2009 Cosmetic Bench Reference; pages 37 to 86), but are not limited to, abrasive, absorbent powder, absorption base, acidulent, activator, adhesion promotor, AHA, alcohol, alcohol ester, analgesic, anesthetic, antacid, anti-acne, anti-aging, anti-bacterial, anti-cracking, anti-cellulite, anti-dandruff, anti-foam, anti-inflammatory, anti-irritant, antimicrobial, antioxidant, antiperspirant, anti-pruritic, antiseptic, antistat agent, astringent, barrier agent, binding agent, hair beaching agent, botanical, buffer agent, calming agent, carrier agent, chelating agent, circulatory stimulant agent, cleansing agent, co-emulsifier agent, colorant, conditioning agent, controlled release agent, cooling agent, co-solvent, coupling agent, denaturant, deodorant, depilatory agent, detangler agent, detergent, disinfectant, dispersant, dye stabilizer, emollient, emulsifier, emulsion stabilizer, enzyme, essential oil, exfoliant, fiber, film former, fixative, flavor, foam booster, foam stabilizer, foaming agent, fragrance, fungicide, gellant, glosser, hair colorant, hair conditioner, hairset polymer, humectant, hydrophobic agent, hydrotropic agents intermediate agent, lathering agent, lubricant, moisture barrier agent, moisturizer, neutralizer, odor-masking agent, oil absorbent agent, ointment base, opacifier, organosilicone, oxidant, oxygen carrier, pearlant agent, perfume solvent, perfume stabilizer, peroxide stabilizer, pigment, plasticizer, polish agent, polymer, polymer film former, powder, preservative, propellant, protein, reducing agent, re-fatting agent, regenerator, resin, scrub agent, sebostatic agent, sequestrant, silicone, silicone replacement, skin calming agent, skin clarifier, skin cleanser, skin conditioner, skin healing agent, skin lightening agent, skin protectant agent, skin purifier agent, skin smoothing agent, skin soothing agent, skin treatment agent, solubilizer, solvent, SPF booster, spreading agent, stabilizer, stimulant agent, sunless tanning agent, sunscreen UVA, sunscreen UVB, super-fatting agent, surfactant, amphoteric surfactant, anionic surfactant, cationic surfactant, non-ionic surfactant, silicone surfactant, suspending agent, sweetener, tanning accelerator, thickener, thixotrope, toner, tonic agent, topical delivery system, vegetable oil, viscosity stabilizer, vitamin, water proofing agent, wax, wetting agent, whitening agent, and wound healing agent. The 2009 Cosmetic Bench Reference (pages 37 to 86) provides examples of ingredient for functional class. This information is also available; and is regularly updated by the addition of new ingredients (and functional classes), at http: / / dir.cosmeticsandtoiletries.com / search / cbr_ing.html.

[0104] In a particular aspect the non-cyclic peptide can be encapsulated in cosmetically acceptable formulations, and especially formulations using a lipid membrane, such as liposomes, microcapsules, nanocapsules, microparticles, and nanoparticles delivery systems. A description of some cosmetically acceptable cosmetic delivery systems can be found in Maherani et al, "Liposomes: A Review of Manufacturing Techniques and Targeting Strategy", Current Nanoscience; 7:436-452 (2011 ). A preferred method of liposome manufacturing is shear method. Preferred cosmetic delivery systems resemble naturally occurring membranes, are flexible, and can penetrate interstitial spaces between cells. It is further contemplated that cosmetic delivery systems may have monolayer, bilayer (e.g. unilammellar vesicle or ULV), or multi layer structures (e.g. multilammerlar vesicle or MLV). Additionally, multilayer liposomes, microcapsules, microsomes, and nanocapsules may have nested structures (e.g. multivesicular vesicle or MW). Cosmetic delivery systems used in the topical formulations can range in size from 500 nm to 10 microns. In the preparation of cosmetic delivery systems, all cosmetically acceptable lipid compositions are contemplated, especially pharmaceutically acceptable lipids. In most instances preferred cosmetic delivery systems comprise amphipathic or amphiphilic molecules such as phospholipids or combinations of phospholipids (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylserine, and phosphoinositides). Additionally, in some instances contemplated cosmetic delivery systems can contain additive(s) such as sterols, polyethylene glycol, cholesterol, dicethylphosphate, stearyl amine, etc. With respect to the amount of delivery systems incorporated in each ready-to-use formulation, the cosmetic delivery system content will typically be adjusted toachieve a sub-antimicrobial concentration of defensins within a preferred range. Unilamellar vesicles / liposomes can be produced using high shear techniques. These vesicles have a greater Zeta Potential than the typical liposome, which allows for smaller, more uniform particle size with increased stability. Zeta Potential is an indicator of the electronic charge on the surface of any macroscopic material that is in contact with a liquid. This can be used to predict and control the stability of suspensions; the higher the Zeta Potential, the greater the stability of the molecule because the charged particles are able to repel and overcome their innate affinity to assemble.

[0105] Preferred cosmetically acceptable carriers include liposomes, nanoparticles, microparticles, and emulsions.

[0106] In a preferred aspect, the non-cyclic peptide is present in the composition in a concentration of about 0.01 pM to about 30 pM, preferably about 0.01 to 10 pM, more preferably about 0.05 pM to about 10 pM, more preferably about 0.1 pM to about 10 pM, more preferably about 0.2 pM to about 10 pM, more preferably about 0.3 pM to about 10 pM, more preferably about 0.5 pM to about 10 pM, more preferably about 1 to 10 pM, or about 0.05 pM to about 5 pM, more preferably about 0.1 pM to about 2.5 pM, even more preferably about 0.2 pM to about 1 pM, more preferably about 0.3 pM to about 1 pM most preferably about 0.5 pM to about 1 pM. More preferably, the non-cyclic peptide is present in the composition in a concentration of 0.01 pM to 10 pM, preferably 0.05 pM to 5 pM, more preferably 0.1 pM to 3 pM more preferably 0.1 pM to 2.5 pM, even more preferably 0.2 pM to 1 pM, more preferably 0.3 pM to 1 pM and most preferably 0.5 pM to about 1 pM.

[0107] In a particular aspect, the cosmetic composition comprises at least one additional cosmetically active agent. Such cosmetically active agent is preferably selected from brightening agents, anti-redness agents, sunscreens and UV organic or inorganic filters, hydrating agents, moisturizers, humectants, exfoliants, anti-wrinkle agents, anti-ageing agents, slimming agents, anti-acne agents, anti-inflammatory agents, antioxidants, radical scavengers, self tanning agents, depilation or shave agents, hair growth moderators, tightening agents, peptides, vitamins and / or myorelaxing agents.

[0108] Preferably the cosmetic composition comprises at least one myorelaxing agent, preferably a mu-conotoxin, more preferably a mu-conotoxin of SEQ ID NO: 14 preferably wherein the first amino acid glutamic acid is in the form of pyroglutamic acid (pGlu), even more preferably mu-conotoxin CnIIIC, as described in WO2013156064, which is incorporated herein by reference.Non-therapeutic uses

[0109] The non-cyclic peptides such as described above are advantageously used for the non-therapeutic preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject.

[0110] In a particular aspect the non-therapeutic preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject comprises the non-therapeutic rejuvenation of the skin, the non- therapeutic prevention of skin ageing (such as photo-ageing), the non-therapeutic strengthening of the skin and / or the reinforcement of the barrier function of the skin in a subject. The present non-cyclic peptides being active as growth factors, they are effective against very diverse consequences of ageing associated with the skin, its appearance, its biomechanical properties and / or its function. Barrier function is preferably defined as the ability of the skin to prevent skin penetration by undesirable organisms or substances, such as viruses, bacteriae, fungi and / or toxin, while allowing penetration of moisture, minerals, vitamins and / or antioxidants.

[0111] In a particular aspect said non-therapeutic rejuvenation of the skin is the reduction and / or treatment of the intrinsic and extrinsic signs of skin ageing, intrinsic signs of ageing being those caused by the elapse of time, whereas extrinsic signs of ageing are those caused by external factors, such sun, pollutants and the like. In another particular aspect, said non-therapeutic prevention of skin ageing is defined as the non-therapeutic prevention of intrinsic and extrinsic signs of skin ageing. Intrinsic and extrinsic signs of skin ageing include wrinkles, especially crow feet’s wrinkles, fine lines, discontinuities of the skin, roughness of the skin, skin sagging, skin color, such as skin redness and skin spots (such as brown spots, red spots and UV spots), and / or loss of brightness of complexion. In an aspect, non-therapeutically reducing and / or bytreating the intrinsic and extrinsic signs of skin ageing comprises improving skin firmness, reducing wrinkle seventy and / or improving skin homogeneity.

[0112] In another particular aspect, the strengthening of the skin comprises improving the biomechanical properties of the skin and / or improving the cohesion between the epidermis and the dermis. Improving the biomechanical properties of the skin preferably include increasing skin elasticity, skin tonicity, skin firmness, dermis thickness, dermis density, sebum content, collagen density, collagen renewal, more preferably increasing skin elasticity, skin firmness, dermis thickness, dermis density, and sebum content.

[0113] Without wishing to be bound by theory, the above-described benefits are achieved by the activation of skin cells, the increase of skin cell growth and proliferation and / or the promotion of skin cell migration. Preferably, the skin cells are fibroblasts and / or keratinocytes, preferably fibroblasts.

[0114] Accordingly, in one aspect the invention relates to a method of activating skin cells, increasing skin cell growth and proliferation and / or the promoting of skin cell migration, wherein the method comprises the step of administering a non- cyclic peptide or composition as described above to a subject. More preferably it relates to a method of activating fibroblasts and / or keratinocytes, increasing fibroblast and / or keratinocyte cell growth and proliferation and / or the promoting of fibroblast and / or keratinocyte migration and / or promoting keratinocyte barrier function, wherein the method comprises the step of administering a non-cyclic peptide or composition as described above to a subject.

[0115] In a particular aspect increase of skin cells activation results in the increase of cell motility, the increase of production of extracellular components and / or the increase of the interactions of epithelial cells with each other. Extracellular components produced by skin cells preferably include extracellular matrix polysaccharides and proteoglycans, glycosaminoglycans, laminins, heparin, heparan sulphate (HSGAGs), chondroitin sulphate, dermatan sulphate (CSGAGs), keratan sulphate and / or hyaluronic acid. In a preferred aspect, the extracellular matrix proteins include collagen, and / or elastin.

[0116] In a preferred aspect, the above-mentioned benefits are achieved by increasing or decreasing expression of at least one gene in fibroblasts and / orkeratinocytes, preferably selected from ACTA2, COL1A1 , COL3A1 , COL5A1 , ELN, FN1 , FBN1 , FBLN5, HAS1 , HAS2, BGN, DCN, SDC1 , COL4A1 , COL4A2, COL6A3, COL7A1 , FGF1 , FGF2, FGF7, VEGFA, VEGFC, CTGF, COMP, EXT2, HS2ST1 , PDPN, THBS1 , B4GALT1 , BMP1 , CCL2, CHST3, CSGALNACT2, IL15RA, LINC00667, PLOD2, TGFB1 , TNC, UST, CDSN, CNFN, IL1 A, IVL, TGM1 , PALLD, COL5A2, P3H1 , EMILIN1 , NID2, IGF1 R, TGFB3, IFIH1 , IL18R1 , CXCL8, CLDN4, EPHB3, ITGB6, SPARC, POSTN, IL6R, IL6ST, EFNB2, OCLN, LAMA3, LAMB3, LAMC2, TIMP2, HBEGF, EREG, FLRT2, ITGA2, ITGA5 ITGA6, DSG2 and / or WNT5A. The gene activation is preferably achieved by activation of TGF[3 pathway on skin cells, preferably on fibroblast and / or keratinocytes. Preferably, TGF[3 pathway is activated by the activation of TGF[3 receptors.Preferably, the TGF[3 receptors are selected from TGF[3 receptor 1 and TGF[3 receptor 2, preferably TGF[3 receptor 1 .

[0117] Accordingly, in one aspect the invention relates to a method of increasing expression of at least one gene in fibroblasts and / or keratinocytes, preferably selected from ACTA2, COL1A1 , COL3A1 , COL5A1 , ELN, FN1 , FBN1 , FBLN5, HAS1 , HAS2, BGN, DCN, SDC1 , COL4A1 , COL4A2, COL6A3, COL7A1 , FGF1 , FGF2, FGF7, VEGFA, VEGFC, CTGF, COMP, EXT2, HS2ST1 , PDPN, THBS1 , B4GALT1 , BMP1 , CCL2, CHST3, CSGALNACT2, IL15RA, LINC00667, PLOD2, TGFB1 , TNC, UST, CDSN, CNFN, IL1 A, IVL, TGM1 , PALLD, COL5A2, P3H1 , EMILIN1 , NID2, IGF1 R, TGFB3, IFIH1 , IL18R1 , CXCL8, CLDN4, EPHB3, ITGB6, SPARC, POSTN, IL6R, IL6ST, EFNB2, OCLN, LAMA3, LAMB3, LAMC2, TIMP2, HBEGF, EREG, FLRT2, ITGA2, ITGA5 ITGA6, DSG2 and / or WNT5A, wherein the method comprises the step of administering a non-cyclic peptide or composition as described above to a subject.

[0118] The above-described benefits are achieved by applying the non-cyclic peptide on the skin of the subject, preferably in the form of a cosmetic composition according to the present invention. Preferably the subject is a human subject.

[0119] The non-cyclic peptide, respectively the cosmetic composition can be applied in various amounts and using various application schemes, depending on the sought benefits, depending on the intensity of defect in skin appearance, biomechanical properties and / or function and / or depending on the intensity of the sought improvement of the skin appearance, biomechanical properties and / orfunction. Preferably, the non-cyclic peptide or the cosmetic composition is applied topically. The non-cyclic peptide or the cosmetic composition can be applied once or repeatedly. Preferably, the non-cyclic peptide or the cosmetic composition is applied daily, preferably twice daily.

[0120] The non-cyclic peptide can be used as sole active compound or in admixture with other active substances. Examples of other substances include mu conotoxin CnIIIC of SEQ ID NO:14, preferably wherein the first amino acid glutamic acid is in the form of pyroglutamic acid (pGlu).

[0121] In a preferred aspect the non-cyclic peptide is used in combination with vitamin C (or a derivative thereof, such as ascorbyl glucoside), Bakuchiol or a combination thereof. Bakuchiol is an ingredient sourced from the leaves and seeds of the Psoralea corylifolia plant. It is used as an anti-ageing substance and has been shown to boost the production of collagen to minimize fine lines and to improve skin smoothness and color. Vitamin C and its derivative ascorbyl glucoside have been used in dermatology and cosmetics as a potent antioxidant, namely and an anti-ageing substance. It is notably known to promote collagen synthesis by fibroblasts. The peptides disclosed herein and vitamin C (or its derivatives, such as ascorbyl glucoside), respectively bakuchiol act synergistically in the activation of various fibroblasts and / or keratinocytes genes, in turn translating into synergistic effects of the activation of these cells, as described herein.

[0122] The non-cyclic peptide or the cosmetic composition can be used in any effective amount. The optimal dose varies depending on the subject and the sought cosmetic effect. In a particular aspect, the non-cyclic peptide (as such or as part of a cosmetic composition) is used in at a dose of 2 pmol per kg of body weight and per day. Lower doses are less preferred due to reduced efficacy. In another particular aspect, the non-cyclic peptide (as such or as part of a pharmaceutical composition) is used in an amount of at most 4 pmol per kg of body weight, preferably at most 0.4 pmol per kg of body weight. Higher doses are less preferred due to the occurrence / increase of adverse effects.Pharmaceutical composition

[0123] The invention relates to a pharmaceutical composition comprising at least one non-cyclic peptide such as described above. Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent and / or excipient. The term "carrier" refers to an organic or inorganic component, of a natural or synthetic nature, in which the active component is combined in order to facilitate, enhance or enable application. According to the invention, the term "carrier" also includes one or more compatible solid or liquid fillers, diluents or encapsulating substances, which are suitable for administration to a patient.

[0124] Possible carrier substances for parenteral administration are e.g. sterile water, Ringer, Ringer lactate, sterile sodium chloride solution, polyalkylene glycols, hydrogenated naphthalenes and, in particular, biocompatible lactide polymers, lactide / glycolide copolymers or polyoxyethylene / polyoxy- propylene copolymers.

[0125] The term "excipient" when used herein is intended to indicate all substances which may be present in a composition described herein and which are not active ingredients such as, e.g., carriers, binders, lubricants, thickeners, surface active agents, preservatives, emulsifiers, buffers, flavoring agents, or colorants.

[0126] The excipient of the composition can be any pharmaceutically acceptable excipient, including specific carriers able to target specific cells or tissues. As stated earlier, possible pharmaceutical compositions include those suitable for oral, rectal, topical, transdermal, buccal, sublingual, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. For these formulations, conventional excipients can be used according to techniques well known by those skilled in the art. The compositions for parenteral administration are generally physiologically compatible sterile solutions or suspensions, which can optionally be prepared immediately before use from solid or lyophilized form. For oral administration, the composition can be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations, such as syrups, elixirs, and concentrated drops. Nontoxic solid carriers or diluents may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and thelike. For compressed tablets, binders, which are agents, which impart cohesive qualities to powdered materials, are also necessary. For example, starch, gelatine, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders. Disintegrants are also necessary in the tablets to facilitate break-up of the tablets. Disintegrants include starches, clays, celluloses, algins, gums and cross-linked polymers. Moreover, lubricants and glidants are also included in the tablets to prevent adhesion of the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture. Colloidal silicon dioxide is most commonly used as a glidant and compounds, such as talc or stearic acid are most commonly used as lubricants. For transdermal administration, the composition can be formulated into ointment, cream or gel form and appropriate penetrants or detergents could be used to facilitate permeation, such as dimethyl sulfoxide, dimethyl acetamide and dimethylformamide. For transmucosal administration, nasal sprays, rectal or vaginal suppositories can be used. The active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate.

[0127] In a particular aspect the pharmaceutical composition further comprises one or more additional active compound. In an aspect the pharmaceutical composition comprises a myorelaxing agent, preferably a mu-conotoxin, more preferably a mu-conotoxin of SEQ ID NO: 14 preferably wherein the first amino acid glutamic acid is in the form of pyroglutamic acid (pGlu), even more preferably mu-conotoxin CnIIIC, as described in WO2013156064, which is incorporated herein by reference.

[0128] In a preferred aspect the pharmaceutical composition further comprises vitamin C (or a derivative thereof, such as ascorbyl glucoside), Bakuchiol or a combination thereof. Bakuchiol is an ingredient sourced from the leaves and seeds of the Psoralea corylifolia plant. It is used as an anti-ageing substance and has been shown to boost the production of collagen to minimize fine lines and to improve skin smoothness and color. Vitamin C and its derivative ascorbyl glucoside have been used in dermatology and cosmetics as a potent antioxidant,namely and an anti-ageing substance. The peptides disclosed herein and vitamin C (or its derivatives, such as ascorbyl glucoside), respectively bakuchiol act synergistically in the activation of various fibroblasts and / or keratinocytes genes, in turn translating into synergistic effects of the activation of these cells, as described herein.First medical use

[0129] In aspect, the invention relates to a non-cyclic peptide of the invention, as described in any of the embodiments of the section directed to non-cyclic peptides as products, such as a non-cyclic peptides having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof for use in therapy or for use as a medicament.

[0130] In other words, the present invention relates to the use of a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23, or to a variant or derivative thereof, or of b. a pharmaceutical composition of the invention, for the manufacture of a medicament.

[0131] In still other words, the invention provides a method for treating a disease or disorder comprising administering a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof; orb. a pharmaceutical composition of the invention to an individual in need thereof.

[0132] In still other words, the invention relates to the use of a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof, preferably at least 86%, such as 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23 or to a variant or derivative thereof; or of b. a pharmaceutical composition of the invention for treating a disease or disorder in a subject in need thereof.

[0133] Preferably the subject to which the peptide or pharmaceutical composition is administered is a human.

[0134] The non-cyclic peptide or the pharmaceutical composition can be used in any therapeutically effective amount. The optimal dose varies depending on the subject and the disease or disorder to be treated, prevented or ameliorated. In a particular aspect, the non-cyclic peptide (as such or as part of a pharmaceutical composition) is used in at a dose of 2pmol per kg of body weight and per day. Lower doses are less preferred due to reduced efficacy. In another particular aspect, the non-cyclic peptide (as such or as part of a pharmaceutical composition) is used in an amount of at most 4 pmol per kg of body weight, preferably at most 0.4 pmol per kg of body weight. Higher doses are less preferred due to the occurrence / increase of adverse effects.

[0135] In a preferred aspect the non-cyclic peptide is administered in combination with vitamin C (or a derivative thereof, such as ascorbyl glucoside), Bakuchiol or a combination thereof. Bakuchiol is an ingredient sourced from the leaves and seeds of the Psoralea corylifolia plant. It is used as an anti-ageing substance and has been shown to boost the production of collagen to minimize fine lines and to improve skin smoothness and color. Vitamin C and its derivative ascorbyl glucoside have been used in dermatology and cosmetics as a potent antioxidant, namely and an anti-ageing substance. The peptides disclosed herein and vitaminC (or its derivatives, such as ascorbyl glucoside), respectively bakuchiol act synergistically in the activation of various fibroblasts and / or keratinocytes genes, in turn translating into synergistic effects of the activation of these cells, as described herein.Second and further medical uses

[0136] The present invention provides for a non-cyclic peptide such as described herein above in the section directed to the general definition of non-cyclic peptides or a pharmaceutical as described herein for use in promoting healing in soft and hard tissues and / or for use as an immunosuppressive agent in a subject in need thereof.

[0137] In other words, the present invention relates to the use of a non-cyclic peptide as described herein or of a pharmaceutical composition of the invention for the manufacture of a medicament for promoting healing in soft and / or hard tissue and / or for the manufacture of an immunosuppressive medicament.

[0138] In still other words, the invention provides a method for promoting healing in soft and / or hard tissue and / or for providing an immunosuppressive effect in a subject in need thereof, comprising administering a non-cyclic peptide as described therein or of a pharmaceutical composition of the invention to the subject.

[0139] In still other words, the invention relates to the use of a non-cyclic peptide as described herein or of a pharmaceutical composition of the invention for promoting healing in soft and / or hard tissue and / or for providing an immunosuppressive effect in a subject in need thereof, comprising administering a non-cyclic peptide as described therein or of a pharmaceutical composition of the invention to the subject.

[0140] Preferably the subject to which the peptide or pharmaceutical composition is administered is a human.

[0141] Due to its efficiency in promoting healing in soft and hard tissues, the non- cyclic peptide and the pharmaceutical composition as described herein are also for use in preventing, ameliorating and / or treating a disease or disorder selected from wound, venous stasis, pressure ulcer, mucositis, fractures and ischemiareperfusion injuries. In a preferred aspect, the wound is a wound with impairedhealing. Although the non-cyclic peptide and the pharmaceutical composition described herein are for use in healing of any kind of wound, the wound is preferably a cutaneous wound. In an aspect, the non-cyclic peptide or the pharmaceutical composition is for improving the rate of healing and / or wound strength, preferably in cutaneous wounds. The non- cyclic peptide and the pharmaceutical composition herein described are particularly advantageous in subjects treated with corticosteroids, antineoplastic agents and / or radiation and / or in diabetic and / or aged subjects.

[0142] In a particular aspect of the invention the non-cyclic peptide or the pharmaceutical composition is for use in reducing the severity and the duration of mucositis, preferably of chemotherapy-induced mucositis.

[0143] In another particular aspect of the invention the non-cyclic peptide or the pharmaceutical composition is for use in accelerating the repair of bone defects and / or increasing bone formation.

[0144] In another particular aspect of the invention the non-cyclic peptide or the pharmaceutical composition is for use in protecting tissues from ischemiareperfusion injury, for reducing the infarct size in a subject with stroke and / or for reducing cardiac necrosis in a subject with coronary artery occlusion. The non- cyclic peptide or the pharmaceutical composition can either be administered before or after the stroke. Preferably it is administered before or within 5 hours, or 4 hours or 3 hours, preferably 2 hours after stroke. In subjects with coronary artery occlusion, the non-cyclic peptide or the pharmaceutical composition is preferably administered following coronary occlusion and before reperfusion. In subjects with coronary artery occlusion, the non-cyclic peptide or the pharmaceutical composition is preferably administered by the intravenous route.

[0145] Due to its efficiency as an immunosuppressive agent, the non-cyclic peptide and the pharmaceutical composition as described herein are also for use in the treatment, amelioration and / or prevention of autoimmune / inflammatory diseases and for use in the prevention or attenuation of transplants rejection in a subject in need thereof. In a particular aspect, the non-cyclic peptide or pharmaceutical composition is for use in the treatment, amelioration and / or prevention of multiple sclerosis, arthritis, rosacea and / or colitis, preferably multiple sclerosis, arthritisand / or colitis. For the sake of the present invention the immunosuppressive effect includes an anti-inflammatory effect.

[0146] In a particular aspect, the multiple sclerosis is allergic encephalomyelitis (EAE). In another particular aspect arthritis is collagen-induced arthritis.

[0147] In another particular aspect, colitis is T helper cell type 1 -mediated colitis. Although the non-cyclic peptide or pharmaceutical composition can be administered by various routes, it is preferably administered by the intranasal route for the prevention, amelioration or treatment of colitis.

[0148] In still another particular aspect, the transplant rejection is acute rejection. Although the non-cyclic peptide or pharmaceutical composition can be administered by various routes, it is preferably administered by the intramuscular route for the prevention or attenuation of transplant rejection.

[0149] The subject is an individual, preferably a mammal, most preferably a human subject, which is in need of therapy due to a disease or disorders such as described above.

[0150] The non-cyclic peptide or the pharmaceutical composition can be used in any therapeutically effective amount. The optimal dose varies depending on the subject and the disease or disorder to be treated, prevented or ameliorated. In a particular aspect, the non-cyclic peptide (as such or as part of a pharmaceutical composition) is used in at a dose of 2pmol per kg of body weight and per day. Lower doses are less preferred due to reduced efficacy. In another particular aspect, the non-cyclic peptide (as such or as part of a pharmaceutical composition) is used in an amount of at most 4 pmol per kg of body weight, preferably at most 0.4 pmol per kg of body weight. Higher doses are less preferred due to the occurrence / increase of adverse effects.

[0151] In a preferred aspect the non-cyclic peptide is administered in combination with vitamin C (or a derivative thereof, such as ascorbyl glucoside), Bakuchiol or a combination thereof. Bakuchiol is an ingredient sourced from the leaves and seeds of the Psoralea corylifolia plant. It is used as an anti-ageing substance and has been shown to boost the production of collagen to minimize fine lines and to improve skin smoothness and color. Vitamin C and its derivative ascorbyl glucoside have been used in dermatology and cosmetics as a potent antioxidant,namely and an anti-ageing substance. The peptides disclosed herein and vitamin C (or its derivatives, such as ascorbyl glucoside), respectively bakuchiol act synergistically in the activation of various fibroblasts and / or keratinocytes genes, in turn translating into synergistic effects of the activation of these cells, as described herein.

[0152] List of embodiments1 ) A non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23, preferably SEQ ID NO: 3 to 7, preferably SEQ ID NO: 4 or 6, preferably SEQ ID NO:4, or to a variant or derivative thereof.2) ! non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23, preferably SEQ ID NO:3 to 7, preferably SEQ ID NO: 4 or 6, preferably SEQ ID NO:4, or to a variant or derivative thereof for use in therapy or for use as a medicament.3) A cosmetic composition comprising a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof.4) A cosmetic composition according to embodiment 3, further comprising vitamin C (or a derivative thereof such as ascorbyl glucoside) and / or bakuchiol.5) Non-therapeutic use of a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23, or to a variant or derivative thereof; or of b. a pharmaceutical composition according to embodiment 3 or 4 for the preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject.) The non-therapeutic use of embodiment 5, wherein the non-cyclic peptide is used in combination with vitamin C (or a derivative thereof such as ascorbyl glucoside) and / or bakuchiol. ) The non-therapeutic use of embodiment 5 or 6, wherein the non-therapeutic preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject comprises the non- therapeutic rejuvenation of the skin, the non-therapeutic prevention of skin ageing, the non-therapeutic strengthening of the skin and / or the reinforcement of the barrier function of the skin in a subject. ) The non-therapeutic use of embodiment 7, wherein the non-therapeutic rejuvenation of the skin is the reduction and / or treatment of the intrinsic and extrinsic signs of skin ageing. ) The non-therapeutic use of embodiment 8, wherein the intrinsic and extrinsic signs of skin ageing include wrinkles, especially crow feet’s wrinkles, fine lines, discontinuities of the skin, roughness of the skin, skin sagging, skin color, such as skin redness and skin spots, and / or loss of brightness of complexion. 0)The non-therapeutic use of embodiment 7, wherein the strengthening of the skin comprises improving the biomechanical properties of the skin and / or improving the cohesion between the epidermis and the dermis. 1 )The non-therapeutic use of embodiment 7, wherein the biomechanical properties of the skin are skin elasticity, skin tonicity, skin firmness, dermis thickness, dermis density, sebum content, collagen density, improved collagen renewal, more preferably skin elasticity, skin firmness, dermis thickness, dermis density, and sebum content. 2)The non-therapeutic use of any one of embodiment 5 to embodiment 11 , wherein the preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject is achieved by the activation of skin cells, the increase of skin cell growth and proliferation and / or the promotion of skin cell migration. 3)The non-therapeutic use of embodiment 12, wherein the increase of skin cells activation results in the increase of cell motility, the increase of production ofextracellular components and / or the increase of the interactions of epithelial cells with each other. )The non-therapeutic use of embodiment 13, wherein the extracellular components produced by skin cells are selected from the group consisting of epithelial matrix polysaccharides and proteoglycans, glycosaminoglycans, laminins, heparin, heparan sulphate (HSGAGs), chondroitin sulphate, dermatan sulphate (CSGAGs), keratan sulphate, hyaluronic acid and combinations thereof.)The non-therapeutic use of any one of embodiment 5 to embodiment 14, wherein the preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject is achieved by increasing expression of at least one gene in fibroblasts and / or keratinocytes, said gene being preferably selected from ACTA2, COL1A1 , COL3A1 , COL5A1 , ELN, FN1 , FBN1 , FBLN5, HAS1 , HAS2, BGN, DCN, SDC1 , COL4A1 , COL4A2, COL6A3, COL7A1 , FGF1 , FGF2, FGF7, VEGFA, VEGFC, CTGF, COMP, EXT2, HS2ST1 , PDPN, THBS1 , B4GALT1 , BMP1 , CCL2, CHST3, CSGALNACT2, IL15RA, LINC00667, PLOD2, TGFB1 , TNC, UST, CDSN, CNFN, IL1A, IVL, TGM1 , PALLD, COL5A2, P3H1 , EMILIN1 , NID2, IGF1 R, TGFB3, IFIH1 , IL18R1 , CXCL8, CLDN4, EPHB3, ITGB6, SPARC, POSTN, IL6R, IL6ST, EFNB2, OCLN, LAMA3, LAMB3, LAMC2, TIMP2, HBEGF, EREG, FLRT2, ITGA2, ITGA5 ITGA6, DSG2 and / or WNT5A. )The non-therapeutic use of any one of embodiment 5 to embodiment 15, wherein the TGF[3 inducible gene activation is achieved by activation of TGF[3 pathway on skin cells, preferably on fibroblast and / or keratinocytes. )The non-therapeutic use of any one of embodiment 5 to embodiment 16, wherein the non-cyclic peptide is used in combination with mu conotoxin CnIIIC of SEQ ID NO: 14, preferably wherein the first amino acid glutamic acid is in the form of pyroglutamic acid (pGlu). )A pharmaceutical composition comprising a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof.)A pharmaceutical composition according to embodiment 18, wherein the pharmaceutical composition further comprises Vitamin C (or a derivative thereof such as ascorbyl glucoside) and / or bakuchiol. )A non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:1 to 13, 15 or 20, or to a variant or derivative thereof, or a pharmaceutical composition according to embodiment 18 or 19 for use in promoting healing in soft and hard tissues and for use as an immunosuppressive agent in a subject in need thereof.)The non-cyclic peptide or pharmaceutical composition for use according to embodiment 20, wherein promoting healing in soft and hard tissues consists in preventing, ameliorating and / or treating a disease or disorder selected from wound, venous stasis, pressure ulcer, mucositis, fractures and ischemiareperfusion injuries. )The non-cyclic peptide or pharmaceutical composition for use according to embodiment 21 , wherein the wound is a cutaneous wound. )The non-cyclic peptide or pharmaceutical composition for use according to embodiment 21 or embodiment 22, wherein the wound is with impaired healing.)The non-cyclic peptide or pharmaceutical composition for use according to embodiment 23, wherein the wound is in a subject treated with corticosteroids, antineoplastic agents and / or radiation and / or in diabetic and / or aged subject.)The non-cyclic peptide or pharmaceutical composition for use according to embodiment 20, wherein the immunosuppressive agent is for use in the treatment, amelioration and / or prevention of autoimmune diseases and for use in the prevention or attenuation of transplants rejection in a subject in need thereof.)The non-cyclic peptide or pharmaceutical composition for use according to embodiment 25, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, arthritis and colitis. )The non-cyclic peptide for use according to any one of embodiments 2 or 20 to 26, wherein the non-cyclic peptide is administered in combination with vitamin C (or a derivative thereof such as ascorbyl glucoside) and / or bakuchiol.)The cosmetic composition according to embodiment 3 or 4, the non-therapeutic use according to any one of embodiment 5 to embodiment 17, the pharmaceutical composition according to embodiment 18 or 19 or the non-cyclic peptide for use according to any one of embodiment 2 or 20 to 27, wherein the non-cyclic peptide has a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23 or to a variant or derivative thereof. )The cosmetic composition according to embodiment 3 or 4, the non-therapeutic use according to any one of embodiment 5 to embodiment 17, the pharmaceutical composition according to embodiment 18 or 19 or the non-cyclic peptide for use according to any one of embodiments 2 or 20 to 27, wherein the peptide is defined as a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:2 and 8 to 13 or to a variant or derivative thereof, and preferably defined as a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:2 and 8 to 13, or to a variant or derivative thereof. )The cosmetic composition according to embodiment 3 or 4, the non-therapeutic use according to any one of embodiment 5 to embodiment 17, the pharmaceutical composition according to embodiment 18 or 19 or the non-cyclic peptide for use according to any one of embodiments 2 or 20 to 27, wherein the peptide is defined as a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:9, or to a variant or derivative thereof, and preferably defined as a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:9, or to a variant or derivative thereof. )The cosmetic composition according to embodiment 3 or 4, the non-therapeutic use according to any one of embodiment 5 to embodiment 17, the pharmaceutical composition according to embodiment 18 or 19 or the non-cyclic peptide for use according to any one of embodiments 2 or 20 to 27, wherein the peptide binds to TGF[3-Receptor 1 (TGFb-R1 ) with a half-maximal receptor binding concentration of from about 5 ng / ml to about 100 ng / ml, preferably from about 20 ng / ml to about 60 ng / ml, more preferably from about 25 ng / ml to about35 ng / ml and / or to TGF[3-Receptor 2 (TGFb-R2) with a half-maximal receptor binding of from about 200 ng / ml to about 800 ng / ml, preferably from about 400 ng / ml to about 700 ng / ml, more preferably from about 550 ng / ml to about 650 ng / ml. )A cosmetic composition according to any one of embodiment 3 or 4 and embodiment 28 to 31 , further comprising at least one cosmetically acceptable carrier, diluent and / or adjuvant, preferably a cosmetically acceptable carrier selected from liposomes, nanoparticles, microparticles and emulsions. )A cosmetic composition according to any one of embodiment 3 or 4 and embodiment 28 to 32, further comprising at least one cosmetically active agent selected from brightening agents, anti-redness agents, sunscreens and UV organic or inorganic filters, hydrating agents, moisturizers, humectants, exfoliants, anti-wrinkle agents, anti-ageing agents, slimming agents, anti-acne agents, anti-inflammatory agents, antioxidants, radical scavengers, self tanning agents, depilation or shave agents , hair growth moderators, tightening agents, peptides, vitamins and / or myorelaxing agents. )A cosmetic composition according to embodiment 33, wherein the myorelaxing agent is mu conotoxin CnIIIC of SEQ ID NO: 14, preferably wherein the first amino acid glutamic acid is in the form of pyroglutamic acid (pGlu). )A cosmetic composition according to any one of embodiment 3 or 4 and embodiment 31 to 34, wherein the non-cyclic peptide is present in a concentration of about 0.01 pM to about 30 pM, preferably about 0.01 to 10 pM, more preferably about 0.05 pM to about 10 pM, more preferably about 0.1 pM to about 10 pM, more preferably about 0.2 pM to about 10 pM, more preferably about 0.3 pM to about 10 pM, more preferably about 0.5 pM to about 10 pM, more preferably about 1 to 10 pM, or about 0.05 pM to about 5 pM, more preferably about 0.1 pM to about 2.5 pM, even more preferably about 0.2 pM to about 1 pM, more preferably about 0.3 pM to about 1 pM most preferably about 0.5 pM to about 1 pM, for example in a concentration of 0.01 pM to 10 pM, preferably 0.05 pM to 5 pM, more preferably 0.1 pM to 3 pM more preferably 0.1 pM to 2.5 pM, even more preferably 0.2 pM to 1 pM, more preferably 0.3 pM to 1 pM and most preferably 0.5 pM to about 1 pM.36)A method of activating skin cells, increasing skin cell growth and proliferation and / or the promoting of skin cell migration, wherein the method comprises the step of administering a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23, or to a variant or derivative thereof, or b. a composition according to any one of embodiments 1 to 30 to a subject, preferably a human subject.37)A method of increasing expression of at least one fibroblasts and / or keratinocytes gene, preferably selected from ACTA2, COL1A1 , COL3A1 , COL5A1 , ELN, FN1 , FBN1 , FBLN5, HAS1 , HAS2, BGN, DON, SDC1 , COL4A1 , COL4A2, COL6A3, COL7A1 , FGF1 , FGF2, FGF7, VEGFA, VEGFC, CTGF, COMP, EXT2, HS2ST1 , PDPN, THBS1 , B4GALT1 , BMP1 , CCL2, CHST3, CSGALNACT2, IL15RA, LINC00667, PLOD2, TGFB1 , TNC, UST, CDSN, CNFN, IL1 A, IVL, TGM1 , PALLD, COL5A2, P3H1 , EMILIN1 , NID2, IGF1 R, TGFB3, IFIH1 , IL18R1 , CXCL8, CLDN4, EPHB3, ITGB6, SPARC, POSTN, IL6R, IL6ST, EFNB2, OCLN, LAMA3, LAMB3, LAMC2, TIMP2, HBEGF, EREG, FLRT2, ITGA2, ITGA5 ITGA6, DSG2 and / or WNT5A, wherein the method comprises the step of administering a. a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23, or to a variant or derivative thereof, or b. a composition according to any of embodiments 3, 4 or 28 to 35 to a subject.38)The method according to embodiment 36 or 37, further comprising administering vitamin C (or a derivative thereof such as ascorbyl glucoside) and / or bakuchiol.ExamplesExample 1 : Synthesis of non-cyclic peptides

[0153] Non-cyclic peptides used in the present invention and comparative non-cyclic peptides listed in [Table 1] below were nano-synthesized from the sequenceselected natural protein analogues using standard synthesis methods.Consensus sequences were defined for the non-cyclic peptides used in the present invention, as provided in [Table 1],

[0154] [Table 1]

[0155] Although these peptides bear many positive charges, the clustering of these charges is only moderate, and there is no amphiphilic character in these peptides (contrarily to alpha- or beta-defensins, or other typical antimicrobial peptides).

[0156] Example 2: Molecular binding microarray

[0157] The non-cyclic peptides of Example 1 were covalently immobilized onto glass microarrays (JPT Technologies). An optimized hydrophilic linker moiety was inserted between the glass surface and the peptide to avoid false negatives caused by steric hindrances. As positive control, TGF[31 was also immobilized on microarrays.

[0158] Recombinant receptors (TGFbRI & TGFbR2 extracellular domains as Fc dimer, and integrin a1131 & a2|31 extracellular domain heterodimers), commercially available in soluble formats, and HSA as control, were directly labelled with a fluorophore (Dylight 650 microscale labelling kit), incubated (from 1 to 1000 ng / mL) with the peptide microarrays for 120 minutes at 30°C, and rinsed with Low-cross buffer (Candor) for 15 minutes at 30°C. Microarrays were scanned using a high-resolution fluorescence scanner. The resulting images were analysed and quantified using spot-recognition software GenePix (Molecular Devices). For each spot, the mean signal intensity was extracted (between 0 and 65535 arbitrary units).

[0159] Peptides were considered as binders when the receptor / HSA signal ratio exceeded 3, and were considered as high-binders when over 10, at the optimal concentration with the largest dynamic range.

[0160] The results are presented in [Table 2] below. When binding could not be determined, “ND” is used.

[0161] [Table 2]: Characterization of the binding of the non-cyclic peptides ofExample 1 to labelled TGFbRI* or TGFbR2*

[0162] These results demonstrate that the non-cyclic peptides of SEQ ID NO: 4 to 13 successfully bind to TGFbRI & TGFbR2 receptors and therefore are expected to exhibit TGF|3-like activity.Example 3: Functional assay: procollagen 1 synthesis

[0163] The non-cyclic peptides of SEQ ID NO:9 and of SEQ ID NO: 13 (designated NP-716 and NP-711 in [Fig. 1 ] and [Fig. 2]) were tested for their ability to modulate procollagen type I expression by normal adult human fibroblasts in mono-layered cultures.

[0164] Confluent cells were incubated for 48 hours with the selected peptides or without (negative control). TGF[31 (1 and 10 ng / mL) was used as reference. Procollagen type I was quantified in culture medium using ELISA. Total protein contents in cells lysates were quantified using Bradford assay. The results are provided in [Fig. 1] and [Fig. 2],

[0165] In this experiment, the non-cyclic peptides of SEQ ID NO:9 and of SEQ ID NO: 13 were administered at 3 pM for 48 hours. As shown in [Fig. 1], the non- cyclic peptide of SEQ ID NO: 13 was able to induce a 50% increase of Procollagen 1 synthesis compared to control (p < 2.1 O’3); and the non-cyclic peptide of SEQ ID NO:9 increased Procollagen 1 levels of more than 100% (p < 2.1 O’3), to an extent similar to TGF[3 action.

[0166] The non-cyclic peptide of SEQ ID NO:9 was then tested at increasing concentrations (0.037, 0.11 , 0.33, 1.1 , 3.3, 10, 30 pM) for dose-response effect, after 72 hours of incubation. The results are shown in [Fig. 2], The dose effect of the non-cyclic peptide on the stimulation of procollagen 1 resulted in a calculated EC50 of 2.47 pM. Best results were obtained at 10 pM with stimulation levels equivalent to that of TGF0 (10 ng / mL).Comparison of the non-cyclic peptide of SEQ ID NO:9 with its cyclic analogue

[0167] In a second experiment, normal human dermal fibroblasts, isolated from the labia of one adult donor (woman of Caucasian origin, 21 years old) (NHDF-cadult) (Ref#C-12302, lot 478Z013.3, Promocell) were cultured in FGM™-2 Fibroblast Growth Medium-2 (Cat#C-23020, Promocell) with 2% FBS, Insulin, hFGFb (Growth Medium 2 SupplementMix Cat#C39325, Promocell) and Penicillin-Streptomycin (Cat#15140122, GibcoTM)

[0168] Cells were thawed and cultured on Falcon® plastic cultureware in their complete growth culture medium, at 37°C in a humidified atmosphere of 5% CO2, for 10 days before being used.

[0169] Cells were seeded in 96-well plates (Cat#161093, Thermo Scientific™) at the density of 20’000 cells / well, in their complete culture medium for 18-24 hours before start of the experiment.

[0170] The day of the experiment, complete growth culture medium was replaced, by the assay medium, which consists of growth culture medium FGM™-2 basal with 1 % FBS percentage and Pen-Strep.

[0171] Then, the cells were treated for 72 hours by adding 80pL of assay medium + 20pL of 5X-concentrated solutions of peptides (test peptides or TGF[31 , or of solvent control) to reach the final concentrations.

[0172] At the end of the treatment, supernatants were harvested and frozen. procollagen-1 dosage was performed with the human pro-collagen Ia1 / COLIA1 (Cat#DY6220-05, bio-techne). The principle of the assay is based on a quantitative sandwich enzyme immunoassay technique.

[0173] The non-cyclic peptide of SEQ ID NO:9 (labelled as XEP-716 in [Fig. 3]) and its cyclic analogue (RTD-2) were tested at increasing concentrations (0.3, 1 , 3, 10, 30 pM) for dose-response effect, after 72 hours of incubation. As shown below, the non-cyclic peptide of SEQ ID NO:9 increased Procollagen 1 levels to an extent similar to TGF[3 action. On the contrary, RTD-2 does not result in any increase of procollagen-1 levels, as indicated by the bar charts at a level comparable to that of the untreated condition, irrespective of the dose.Example 4: Functional assay: Collagen fibre synthesis

[0174] In this experiment, the non-cyclic peptide of SEQ ID NO:9 and its cyclic analogue RTD-2 were tested at increasing concentrations (0.3, 1 , 3, 10, 30 pM)for dose-response effect, after 72 hours of incubation for their ability to promote collagen fibre synthesis in fibroblasts.

[0175] Normal human dermal fibroblasts, isolated from the labia of one adult donor (woman of Caucasian origin, 21 years old) (NHDF-c adult) (Ref#C-12302, lot 478Z013.3, Promocell) were cultured in FGMTM-2 Fibroblast Growth Medium-2 (Cat#C-23020, Promocell) with 2% FBS, Insulin, hFGFb (Growth Medium 2 SupplementMix Cat#C39325, Promocell) and Penicillin-Streptomycin (Cat#15140122, GibcoTM).

[0176] Cells were thawed and cultured on Falcon® plastic cultureware in their complete growth culture medium, at 37°C in a humidified atmosphere of 5% CO2, for 10 days before being used.

[0177] Cells were seeded in 96-well plates (Cat#161093, Thermo Scientific™) at the density of 20’000 cells / well, in their complete culture medium for 18-24 hours before start of the experiment.

[0178] The day of the experiment, complete growth culture medium was replaced, by the assay medium, which consists of growth culture medium FGM™-2 basal with 1 % FBS percentage and Pen-Strep.

[0179] Then, the cells were treated for 72 hours by adding 80pL of assay medium + 20 pL of 5X-concentrated solutions of peptides (test peptides or TGF-b1 , or of solvent control) to reach the final concentrations.

[0180] At the end of the treatment, assay media were removed and cells were rinsed with PBS. Then, after one rinse, cells were fixed with Kahle fixative (3.7% formaldehyde, 26.88% Ethanol, 348 mM acetic acid in water) for 10 minutes at room temperature. After fixative being removed and cells being washed in PBS, cells were incubated for 30 minutes in the staining solution containing Sirius Red (Cat#9046, Chondrex). After removal of the staining solution, the cell layer was washed with distilled water repeatedly until the water runs clear. Dye extraction buffer was then added in the wells and dyes were eluted in order to measure the quantity retained by the cell layer by absorbance measurements. Optical Densities were read on an FLUOstar (BMG Labtech) with the following filters: 540 nm (BW 10 nm) and 600 nm (BW 10 nm).

[0181] All measures were performed in triplicate, in a single experiment.

[0182] Optical density measurement of Sirius Red staining was used to quantify total collagen content of the layer of cells in each well.

[0183] Data are expressed as means + / - Standard Error of the Mean (SEM) of the replicates.

[0184] As shown in [Fig. 4], the non-cyclic peptide of SEQ ID NO:9 (labelled as XEP- 716) increased collagen fiber level of about 18% compared to the untreated control condition. On the contrary, treatment with the cyclic analogue RTD-2 only resulted in a small increase in the amount of collagen.Example 5: Functional assay: Hyaluronic acid synthesis

[0185] In this experiment, the non-cyclic peptide of SEQ ID NO:9 (labelled as XEP- 716) and its cyclic analogue RTD-2 were tested at one concentration (5 pM) after 72 hours of incubation for their ability to promote hyaluronic acid synthesis in fibroblasts.

[0186] Normal Human Dermal Fibroblasts, isolated from the labia of one adult donor (woman of Caucasian origin, 21 years old) (NHDF-c adult) (Ref#C-12302, lot 478Z013.3, Promocell) were cultured in FGMTM-2 Fibroblast Growth Medium-2 (Cat#C-23020, Promocell) with 2% FBS, Insulin, hFGFb (Growth Medium 2 SupplementMix Cat#C39325, Promocell) and Penicillin-Streptomycin (Cat#15140122, GibcoTM)

[0187] Cells were thawed and cultured on Falcon® plastic cultureware in their complete growth culture medium, at 37°C in a humidified atmosphere of 5% CO2, for 10 days before being used.

[0188] Cells were seeded in 96-well plates (Cat#161093, Thermo Scientific™) at the density of 20’000 cells / well, in their complete culture medium for 18-24 hours before start of the experiment.

[0189] The day of the experiment, complete growth culture medium was replaced by the assay medium, which consists of growth culture medium FGM™-2 basal with 1 % FBS percentage and Pen-Strep.

[0190] Then, the cells were treated for 72 hours by adding 80pL of assay medium + 20pL of 5X-concentrated solutions of peptides (test peptides or TGF-b1 , or of solvent control) to reach the final concentrations.

[0191] At the end of the treatment, supernatants were harvested and frozen. Hyaluronic acid dosage was performed with the Hyaluronan Quantikine ELISA (Cat#DHYALO, bio-techne). The principle of the assay is based on a quantitative sandwich enzyme immunoassay technique.

[0192] Supernatants were thawed and diluted hundred times with Calibrator Diluent RD5-18. The Hyaluronan standard was reconstituted with Calibrator Diluent RD5- 18 then diluted to produce the standard range. In the 96-well plate pre-coated with recombinant human Aggrecan, all reagents, samples and working standards were mixed with Assay Diluent RD1-14 and incubated for 2 hours at room temperature with agitation. Then five washes were performed with Wash Buffer. Hyaluronan Conjugate (rhAgreccan conjugated to horseradish peroxidase) was added and the plate was incubated for 2 hours at room temperature with agitation. Then five washes were performed. Substrate solution (hydrogen peroxide with tetramethylbenzidine) was added and the plate was incubated 30 minutes at room temperature protected from light. Then Stop Solution (hydrochloric acid) was added.

[0193] Optical Densities were read on an FLUOstar (BMG Labtech) with the following filters: 450 nm (BW 10 nm) and 540 nm (wavelength correction). The data analysis was performed with software MARS (BMG Labtech).

[0194] All measures were performed in triplicate, in a single experiment.

[0195] As shown in [Fig. 5], the non-cyclic peptide of SEQ ID NO:9 (labelled as XEP- 716) increased Hyaluronic acid level of about 100% compared to the untreated control condition. On the contrary, treatment with its cyclic analogue RTD-2 only resulted in a slight increase in the amount of Hyaluronic acid.Example 6: Transcriptomics analysis (NGS)

[0196] To compare the effects of the non-cyclic peptide of SEQ ID NO: 9 (XEP-716) and TGF[3, the transcriptomes of normal adult fibroblasts (NHDF) treated with TGFp (10 ng / mL) or the non-cyclic peptide of SEQ ID NO: 9 (3pM) were analysed using New Generation Sequencing on RNA samples. Untreated cells were used as reference. Differential expression was compared by calculating the fold change ratio between treatments (TGF[3 or the non-cyclic peptide of SEQ ID NO: 9) and control (untreated). The non-cyclic peptide of SEQ ID NO:9 (3pM) wasincubated on normal dermal human fibroblast monolayers following administration to cells. Each peptide was incubated in triplicate for each tested time point.

[0197] After incubation times of 4, 8, 24 and 72 hours, monolayers were rinsed, and RNA was extracted using Qiagen RNeasy minikit. RNA extracts were preserved in cell protect reagent and RNA was quantified using nanodrop technology.

[0198] Before sequencing, a polyA purification step was performed followed library preparation using Illumina TruSeq stranded mRNA kit. Sequencing was performed using Illumina Sequencing - HiSeq High-Output (HO) single read (1 x 150 bp) procedure.

[0199] Analysis of the results was performed with the following process:• Quality check of reads was done with fastqc and a merged report was generated with multiqc (2016, Bioinformatics, 32(19), 3047-3048). The read quality was good for all samples (see separate report for QC).• Reads were mapped on the human genome version hg38 with STAR (2013, Bioinformatics, 29(1), 15-21 ).• Counts were calculated with featureCounts (2014, Bioinformatics, 30(7), 923- 930).• Reference gene positions were extracted from ENSEMBL hg38 annotation file genesCHR.gtf.• Fold changes and statistical analysis were performed with the R package edgeR (2010, Bioinformatices, 26(1 ), 136-140). Low expression genes were filtered out: mean of all samples <1 with samples normalized in counts per million (cpm). 14 384 genes were kept.

[0200] The plot of [Fig. 6] represents the fold-change in expression for the 9368 genes that are up- or down-regulated by TGF0 or the non-cyclic peptide of SEQ ID NO: 9. This assay demonstrates a high correlation (R2= 0.72) between the effect of treatment with TGF0 and with the non-cyclic peptide of SEQ ID NO: 9.

[0201] Furthermore, [Table 3] below shows the level of expression (expressed as gene counts, measured by RNAseq) of particular genes that were differentiallyexpressed by TGF0 and the non-cyclic peptide of SEQ ID NO: 9. It shows similar up- and down-regulation for TGF0 and the non-cyclic peptide of SEQ ID NO: 9.

[0202] [Table 3]Example 7: Permeability on reconstructed skin epidermis

[0203] To estimate skin penetration, a solution containing 20 pM the non-cyclic peptide of SEQ ID NO: 9 was applied on reconstructed epidermis model and incubated for 24 hours, the non-cyclic peptide of SEQ ID NO: 9 was then measured in the receptor fluid that sits at the basolateral side of the epidermis.

[0204] The peptide was applied to the apical side of Episkin skinethic reconstructed human epidermis (x 24 (RHE), Ref. RHE / S / 17, 0.5 cm2) at concentration 50 pM in HBSS supplemented with 300nM BSA. Once applied on the membrane, Lucifer yellow (10 pL, 3 pM) was also added to the apical side.

[0205] At To, the peptide solution (100 pL) was applied to the apical side of 2 RHEs (24 RHEs in total). At T= 1 hour, 2 hours, 4 hours and 6 hours, the basolateral side was sampled (400 pL) and the receptor was replaced with an equivalent volume of HBSS / 300nM BSA. At 6 hours after application, the remaining volume on the apical side was collected and stored for analysis. Samples were stored at 4°C until analysis.

[0206] Cumulated doses of the non-cyclic peptide of SEQ ID NO: 9 (labelled as XEP- 716) collected in the receptor fluid are shown in [Fig. 7], This experiment demonstrates that the non-cyclic peptide of SEQ ID NO: 9 can penetrate the epidermis to reach the target tissue.Example 8: Cosmetic compositions

[0207] A cream was prepared by formulating a composition consisting of 2.5%, respectively 5% w / w of any one of the non-cyclic peptides of SEQ ID NO: 4 to 13 in the vehicle described in [Table 4] below.

[0208] [Table 4]: vehicle of the cosmetic compositionExample 9: Quantification of the anti-wrinkle effects on human

[0209] The clinical evaluation of anti-wrinkle effects of the non-cyclic peptide of SEQ ID NO: 9 was done on a panel of 22 female volunteers aged between 47 and 69 years old (mean aged 61 years old) after repeated application of the product, twice a day for 84 days. Each volunteer applied the cream of Example 8 containing 5% of the non-cyclic peptide of SEQ ID NO: 9 on one hemi-face, and the vehicle cream on the other hemi-face. The panellists were selected for their wrinkles and / or fine lines on the crow’s feet of average to strong intensity.

[0210] Wrinkle severity was assessed using in vivo clinical evaluation by an expert. The expert assessed the main wrinkle depth on the crow’s feet of a subject from a 9 points scale. This scale ranges from 0 (no depth, absence of wrinkles) to 8 (very deep wrinkles).

[0211] The results are shown in [Fig. 8], which shows that repeated application of a cream containing 5% of the active ingredient for 84 days led to a reduction of wrinkle severity. Such effects were not observed with the vehicle cream.Example 10: Quantification of the skin firming effect on human

[0212] The clinical evaluation of skin firming effect of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) was done on the same volunteer panel described in example 9. The panellists displayed a saggy skin with a lack of skin firmness.

[0213] Measurements are taken using the SEM 575 cutometer (Courage & Khazaka). The principle of this technique is based on the creation of negative pressure on the skin’s surface and on the measurement of vertical movement on the induced skin. This movement is determined by an optical system. The quantity of light detected by the sensor is proportional to the movement of the skin’s surface. The measuring area was the face (malar area left and right hemiface).

[0214] The skin firmness is measured through the Ilf parameter. The skin firmness is inversely proportional to the value of Ilf.

[0215] The graph of [Fig. 9] shows that repeated application of a cream containing 5% of the active ingredient for 84 days led to a decrease of Ilf parameter, meaning an improvement of skin firmness. Such effects were not observed with the vehicle cream.Example 11: Quantification of the improvement of skin homogeneity on humans

[0216] The clinical evaluation of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) properties on skin homogeneity was done on the same volunteer panel described in example 9. The panellists displayed a dull complexion on the face.

[0217] The skin homogeneity was measured through image analysis of colorimetric variance on face macrophotographies. A significant decrease in the colorimetric variance corresponds to an improvement in the skin homogeneity.

[0218] The graph of [Fig. 10] shows that repeated application of a cream containing 5% of the active ingredient for 84 days led to a decrease of colorimetric variance, meaning an improvement of skin homogeneity. Such effects were not observed with the vehicle cream.Example 12: Quantification of the improvement of skin firmness and elasticity on human

[0219] The clinical evaluation of the effects of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) on skin biomechanical properties (firmness and elasticity) was done on 2 panels of 25 and 23 female volunteers aged between 40 to 60 years old after repeated applications, twice a day for 56 days, of a cream containing 2.5% or 5% of the active ingredient (non-cyclic peptide of SEQ ID NO: 9). Each volunteer applied the cream containing the active ingredient on one hemi-face, and the vehicle cream on the other hemi-face.

[0220] Skin firmness and elasticity were measured by the use of a cutometer (technic described in the example below) before treatment and after 14, 28 and 56 days of treatment.

[0221] The skin firmness was measured through the Ilf parameter. The skin firmness is inversely proportional to the value of Ilf. The skin elasticity was determined through the Ur parameter.

[0222] The graphs of [Fig. 11] and [Fig. 12] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 14, 28 and 56 days led to a progressive decrease of Ilf parameter, meaning an improvement of skin firmness. Such trend was not observed with the vehicle cream alone.

[0223] The graphs of [Fig. 13] and [Fig. 14] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 14, 28 and 56 days led to a progressive increase of Ur parameter, meaning an improvement of skin elasticity. Such trend was not observed with the vehicle cream alone.Example 13: Quantification of the improvement of dermis density and thickness on human

[0224] The clinical evaluation of the effects of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) on dermis density and thickness was done on the same volunteer panels described in example 12. Dermis density was measured by the use of the Dermascan C ultrasound system (Cortex technology, Denmark) with a special 20 Mhz probe. The dermal density and dermal thickness evaluation were calculated on the B-scan image area. The measuring area was the malar area of the face (left and right hemiface). The density and thickness were measured before and after 28 and 56 days of repeated applications.

[0225] The graphs of [Fig. 15] and [Fig. 16] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 28 and 56 days led to a larger increase of the dermis density than the vehicle alone.

[0226] The graphs of [Fig. 17] and [Fig. 18] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 28 and 56 days led to a larger increase of the dermis thickness than the vehicle alone.Example 14: Study of the rejuvenative properties of the active ingredient through its impact on skin structures at the microscopic level

[0227] The clinical evaluation of skin rejuvenating effect of the active ingredient (the non-cyclic peptide of SEQ ID NO: 9) was done on the same volunteer panels described in example 12.

[0228] The effect of the active ingredient on skin microscopic structure was studied by the use of the confocal Laser Scanning Microscopy (CLSM) system (Vivascope 1500, Mavig, Germany) which allows uniform imaging of the different skin layers: epidermis, Dermo-Epidermal Junction (DEJ) and dermis.

[0229] The measuring area was mainly the malar area of the face, for both hemifaces. In order to follow the same area during the subsequent evaluations, the exact location was specified on volunteers.

[0230] Several parameters were measured: the thicknesses of dermal epidermal junction, the density of edged papillae, the perimeter of collagen fibers (for youngcollagen fibers and total fibers). The edged papillae are visualized by confocal imaging through their unique pattern consisting of a demarcated rim of bright basal cells (J Am Acad Dermatol. 2021 Jan; 84(1 ): 102-119. Doi:10.1016 / j.jaad.2020.05.097). Aged skin exhibits slim DEJ with few invaginations in the dermis; additionally, collagen fibers tend to decrease with age, especially the newly synthesized ones. As a results, an increase of the above-mentioned parameters would reflect a rejuvenation of skin microscopic structures.

[0231] The graphs of [Fig. 19] and [Fig. 20] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 14, 28 and 56 days led to a progressive increase of the DEJ thickness. This increase means a rejuvenation of the skin microscopic structures. Such trend was not observed with the vehicle cream.

[0232] The graphs of [Fig. 21] and [Fig. 22] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 14, 28 and 56 days led to a progressive increase of the edged papillae density. This increase means a rejuvenation of the skin microscopic structures. Such trend was not observed with the vehicle cream.

[0233] The graphs of [Fig. 23] and [Fig. 24] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively for 14, 28 and 56 days led to a progressive increase of the perimeter of young collagen fibers. This effect is also translated at the level of total collagen fibers (see [Fig. 25] and [Fig. 26], demonstrating that the active ingredient is able to stimulate collagen synthesis in the skin. Such trend was not observed with the vehicle cream.Example 15: Study of the effect of the active ingredient on skin barrier function

[0234] The clinical evaluation of the effect of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) on skin barrier function was done on the same volunteer panels described in example 12. The stratum corneum (SC) thickness was measured with the confocal Laser Scanning Microscopy (CLSM) system (Vivascope 1500, Mavig, Germany).

[0235] The graphs of [Fig. 27] and [Fig. 28] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 14, 28 and56 days led to a progressive increase of SC thickness, meaning a reinforcement of skin barrier function. Such trend was not observed with the vehicle cream.Example 16: Study of the effect of the active ingredient on skin sebum production

[0236] The clinical evaluation of the effect of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) on skin sebum production was done the same volunteer panels described in example 12.

[0237] The quantification of skin lipidic index was obtained with a Sebumeter® system (Courage - Khazaka Electronic GmbH). The amount of sebum is measured by a mat tape that is brought into contact with the skin of the malar area of the face. The tape becomes transparent in relation with sebum levels of the sampled area. Then, tape sebum content is measured based on grease spot photometry.

[0238] The graphs of [Fig. 29] and [Fig. 30] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 56 days led to an increase of skin lipidic index, meaning a reinforcement of skin barrier function and skin hydration properties.Example 17: Study of the effect of the active ingredient on skin redness

[0239] The clinical evaluation of the effect of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) on skin redness was done the same volunteer panels described in example 12.

[0240] Skin redness was evaluated by VISIA systems (Canfield, USA) after obtaining the defined photographs and submitting the series to the proper alignment. The Visia systems (VISIA-CA or VISIA-CR) allow the obtention of standardized photographic images under normal, cross polarized, parallel polarized and UV lamp of both hemifaces and the front before, during and after the treatment with the active or the vehicle in order to quantify the evolution of the active ingredient's effect. The analysis software allows a definition of a Region of Interest and the calculation of the area and number of the red spots.

[0241] The graphs of [Fig.31 ] to [Fig. 33] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 56 days led to adecrease in skin redness as confirmed by the count of the red spots and the measurement of red spots area. No such reduction of skin redness was observed with the vehicle alone.

[0242] Skin redness can have many causes: bums (sunburn), inflammatory skin conditions (eczema, acne, or various dermatitis), infections and some skin conditions such as rosacea or psoriasis or spider veins. The active presented here can improve skin redness found in these various skin conditions.Example 18: Study of the effect of the active ingredient on a major skin photodamage the skin hyper pigmentation

[0243] The clinical evaluation of the effect of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) on skin hyper pigmentation spots was done the same volunteer panels described in example z.

[0244] Skin hyper pigmentated spots was evaluated by VISIA systems (Canfield, USA). The analysis software allows a definition of a Region of Interest and the calculation of the areas and number of the parameters such as brown spots, and UV spots.

[0245] Brown spots which are dark lesions in the skin occur as a result of hyperpigmentation mainly due to long term skin sun exposure (lentigines) or other skin conditions such as melasma. These brown spots are more frequent in aged skins. Moreover, the VISIA device allows the visualization of UV spots which are concentrated areas of melanin in the sub-dermal layer of skin. UV spots cannot be detected by the naked eye. UV spots are spots that occur on the skin due to UV light from natural or artificial origin. UV spots are characteristics of skin photo-damage.

[0246] The graphs of [Fig.34] to [Fig. 39] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 56 days led to a decrease in Brown and UV spots as confirmed by the count of the brown spots and UV spots but also the measurement of brown spots area. Such trend was not observed with the vehicle cream.

[0247] The active presented here can reduce skin hyperpigmentation, a major skin photodamage. Moreover, the effects observed on brown spots (their reduction in number and area) after repeated application of a cream containing 2.5% or 5% ofthe active ingredient, respectively, for 56 days, suggest a skin whitening and lightening property of the active ingredient described here.Example 19: Study of the effect of the active ingredient on skin imperfections

[0248] The clinical evaluation of the effect of the active ingredient (non-cyclic peptide of SEQ ID NO: 9) on skin imperfections was done the same volunteer panels described in example 12.

[0249] The skin imperfections were quantified by the use of the VISIA systems (Canfield, USA). The analysis software allows a definition of a Region of Interest and the calculation of the areas and number of the parameters “visible spots”. "Visible spots" is an umbrella term that encompass skin blemishes (such as freckles, aged spots, red spots. This term refers to brown and red lesions visible on the skin surface that cause irregularities and skin imperfections.

[0250] The graphs of [Fig.40] to [Fig. 42] show that repeated application of a cream containing 2.5% or 5% of the active ingredient, respectively, for 56 days led to a decrease in visible spots. Such trend was not observed with the vehicle cream. The active presented here can reduce skin imperfections to improve the skin tone.Example 20: Transcriptomics analysis (NGS) on several non-cyclic peptides

[0251] To compare the effects of several non-cyclic peptides, the transcriptomes of normal adult fibroblasts (NHDF) treated with different non-cyclic peptides (SEQ ID NO: 9, 4, 6, 15, and 20) were analyzed using New Generation Sequencing on RNA samples. Untreated cells were used as reference. Differential expression was compared by calculating the fold change ratio between treatments. The different non-cyclic peptides were incubated at a concentration of 10pM on normal dermal human fibroblast monolayers following administration to cells. Each treatment was performed in triplicate.

[0252] After an incubation time of 24 hours, monolayers were rinsed, and RNA was extracted using Qiagen RNeasy minikit. RNA extracts were preserved in cell protect reagent and RNA was quantified using nanodrop technology.

[0253] Before sequencing, a polyA purification step was performed followed by library preparation using Illumina TruSeq stranded mRNA kit. Sequencing wasperformed using Illumina Sequencing - HiSeq High-Output (HO) single read (1 x 150 bp) procedure.

[0254] Analysis of the results was performed with the following process:• Quality check of reads was done with fastqc and a merged report was generated with multiqc (2016, Bioinformatics, 32(19), 3047-3048). The read quality was good for all samples (see separate report for QC).• Reads were mapped on the human genome version hg38 with STAR (2013, Bioinformatics, 29(1), 15-21 ).• Counts were calculated with featureCounts (2014, Bioinformatics, 30(7), 923- 930).• Reference gene positions were extracted from ENSEMBL hg38 gtf annotation file.• Fold changes and statistical analysis were performed with the R package edgeR (2010, Bioinformatices, 26(1 ), 136-140). Low expression genes were filtered out: mean of all samples <1 with samples normalized in counts per million (cpm). This procedure kept around 10,000 genes, with small variations according to experiments and cell types.

[0255] [Table 5] below shows the level of change in expression (expressed as fold change of control level, represented as Iog2 - meaning that a value of 1 corresponds to a 2-fold increase compared to untreated condition) of particular genes that were differentially expressed by several non-cyclic peptides. N.s. means that the fold change was not significant. Overall, these results show that the non-cyclic peptides of the invention induce genes important for fibroblast activation and the synthesis of extracellular matrix components.

[0256] [Table 5]

[0257] A similar experiment was conducted with non-cyclic peptides (SEQ ID NO: 9, 11 , 12, 13, 10. The results are provided in [Table 6] below Similar conclusions could be drawn.

[0258] [Table 6]Example 21: Transcriptomics analysis (NGS) on keratinocytes

[0259] To compare the effects of several non-cyclic peptides on keratinocytes, the transcriptomes of human keratinocytes treated with different non-cyclic peptides (SEQ ID NO: 9, 4, 6, 15, 20) were analyzed using New Generation Sequencing on RNA samples. Untreated cells were used as reference. Differential expression was compared by calculating the fold change ratio between treatments. The different non-cyclic peptides were incubated at a concentration of 10pM on keratinocyte monolayers following administration to cells. Each treatment was performed in triplicate.

[0260] Human Keratinocytes, isolated from human adult epidermis (Ref#KER110, Biopredic) were cultured in DermaLife® K Keratinocyte Medium (Ref#LL-0007, Lifeline) with its growth supplement (Insulin, L-glutamine, epinephrine, apotransferrin, TGF-alpha, extract PTM, hydrocortisone hemisuccinate) and antibiotics (gentamicin and amphotericin B). Cells were thawed and cultured on Falcon® plastic cultureware in their complete growth culture medium, at 37°C in a humidified atmosphere of 5% CO2, until 70-80% of confluency. For the NGS assay, cells were seeded in 96-well plates (Cat#161093, Thermo Scientific™) at the density of 40’000 cells / well, in their complete culture medium for 18-24 hours before start of the experiment.

[0261] After incubation times of 24 hours, monolayers were rinsed, and RNA was extracted using Qiagen RNeasy minikit. Similar procedures were then used for sample processing and data analysis.

[0262] [Table 7] below shows the level of change in expression (expressed as fold change of control level, represented as Iog2 - meaning that a value of 1 corresponds to a 2-fold increase compared to untreated condition) of particular genes that were differentially expressed by several non-cyclic peptides. N.s. means that the fold change was not significant. Overall, these results show thatthe non-cyclic peptides of the invention induce genes important for keratinocyte activation, keratinocyte barrier function and the synthesis of extracellular matrix components.

[0263] [Table 7]Example 21 : Mixture of non-cyclic peptides with ascorbyl glucoside

[0264] To compare the effects of the non-cyclic peptide of SEQ ID NO: 9 with that of ascorbyl glucoside, and to explore the effect of the combination of both molecules, the transcriptomes of normal adult fibroblasts (NHDF) and keratinocytes treated with the non-cyclic peptide of SEQ ID NO: 9 (at a concentration of 10pM), or ascorbyl glucoside (Sigma, cat. PHR1433, at a concentration 10mM), or a mixture of both molecules were analyzed using New Generation Sequencing on RNA samples. Untreated cells were used as reference. Differential expression was compared by calculating the fold change ratio between treatments. Each treatment was performed in triplicate.

[0265] After incubation times of 24 hours, monolayers were rinsed, and RNA was extracted using Qiagen RNeasy minikit. Similar procedures were then used for sample processing and data analysis.

[0266] [Table 8] below shows the level of change in expression (expressed as fold change of control level, represented as Iog2 - meaning that a value of 1 corresponds to a 2-fold increase compared to untreated condition) of particular fibroblast genes that were differentially expressed by the non-cyclic peptide ofSEQ ID NO: 9. N.s. means that the fold change was not significant. Overall, these results show that the non-cyclic peptide of SEQ ID NO: 9 and ascorbyl glucoside can have a synergistic effect to induce genes important for fibroblast activation, and their synthesis of extracellular matrix components.

[0267] [Table 8]

[0268] [Table 9] below shows the level of change in expression (expressed as fold change of control level, represented as Iog2 - meaning that a value of 1 corresponds to a 2-fold increase compared to untreated condition) of particular keratinocyte genes that were differentially expressed by the non-cyclic peptide of SEQ ID NO: 9. N.s. means that the fold change was not significant. Overall, these results show that the non-cyclic peptide of SEQ ID NO: 9 and ascorbyl glucoside have a synergistic effect to induce genes important for keratinocyte activation, and keratinocyte barrier function.

[0269] [Table 9]Example 22: Mixture of non-cyclic peptides with Bakuchiol

[0270] To compare the effects of the non-cyclic peptide of SEQ ID NO: 9 with that of bakuchiol, and to explore the effect of the combination of both molecules, the transcriptomes of normal adult fibroblasts (NHDF) and keratinocytes treated with the non-cyclic peptide of SEQ ID NO: 9 (at a concentration of 10pM), or bakuchiol (Cayman, Cat. 11684, at a concentration 20pM), or a mixture of both molecules were analyzed using New Generation Sequencing on RNA samples. Untreated cells were used as reference. Differential expression was compared by calculating the fold change ratio between treatments. Each treatment was performed in triplicate.

[0271] After incubation times of 24 hours, monolayers were rinsed, and RNA was extracted using Qiagen RNeasy minikit. Similar procedures were then used for sample processing and data analysis.

[0272] [Table 10] below shows the level of change in expression (expressed as fold change of control level, represented as Iog2 - meaning that a value of 1 corresponds to a 2-fold increase compared to untreated condition) of particular fibroblast genes that were differentially expressed by the non-cyclic peptide of SEQ ID NO: 9. N.s. means that the fold change was not significant. Overall, these results show that the non-cyclic peptide of SEQ ID NO: 9 and bakuchiolcan have a synergistic effect to induce genes important for fibroblast activation, and their synthesis of extracellular matrix components.

[0273] [Table 10]

[0274] [Table 11] below shows the level of change in expression (expressed as fold change of control level, represented as Iog2 - meaning that a value of 1 corresponds to a 2-fold increase compared to untreated condition) of particular keratinocyte genes that were differentially expressed by the non-cyclic peptide of SEQ ID NO: 9. N.s. means that the fold change was not significant. Overall, these results show that the non-cyclic peptide of SEQ ID NO: 9 and bakuchiol have a synergistic effect to induce genes important for keratinocyte activation, keratinocyte barrier function and the synthesis of extracellular matrix components.

[0275] [Table 11]Sequence Listing Free Text

[0276] SEQ ID NO:1 (Consensus sequence 1 , based on specific sequences 704, 708, 705, 712, 715, 716, 717, 709, 710 and 711 ): R C (V / l / L) C (T / R / G) R (G / R) (F / V / l) C R C (V / F / l / L) C (R / T / G) R.

[0277] SEQ ID NO:2 (Consensus sequence 2, based on specific sequences 715, 716, 717, 709, 710 and 711 ): (G / R) (F / V / l) C R C (V / l / L) C (T / R / G) R (G / R) (F / V / l) C R C (l / L) C (R / T / G) R.

[0278] SEQ ID NO:3 (Consensus sequence 3, based on specific sequences 704, 708, 705, 712): R C (V / l / L) C (T / R / G) R G (F / V) C R C (V / F) C (R / T) R G (V / F) C.

[0279] SEQ ID NO:4 (sequence 704): RCVCTRGFCRCVCRRGVC.

[0280] SEQ ID NO:5 (sequence 708): RCVCTRGFCRCFCRRGVC.

[0281] SEQ ID NO:6 (sequence 705): RCVCRRGVCRCVCRRGVC.

[0282] SEQ ID NO:7 (sequence 712): RCVCRRGVCRCVCTRGFC.

[0283] SEQ ID NO:8 (sequence 715): GFCRCICTRGFCRCICTR.

[0284] SEQ ID NO:9 (sequence 716): GVCRCLCRRGVCRCLCRR.

[0285] SEQ ID NO: 10 (sequence 717): GFCRCLCRRGVCRCICTR.

[0286] SEQ ID NO:11 (sequence 709): GICRCICGRGICRCICGR.

[0287] SEQ ID NO:12 (sequence 710): GICRCICGRRICRCICGR.

[0288] SEQ ID NO: 13 (sequence 711 ): RICRCICGRRICRCICGR.

[0289] SEQ ID NO:14 (sequence of mu-conotoxin CnIIIC): EGCCNGPKGCSSKWCRDHAACC

[0290] SEQ ID NO: 15: (Sequence 713): GICRCICTRGFCRCICVL

[0291] SEQ ID NO:16 (Sequence 714): GICRCLCRRGVCRCICVL

[0292] SEQ ID NO: 17 (Sequence 706): GFCRCVCTRGFCRCVCTR

[0293] SEQ ID NO: 18 (Sequence 707): GFCRCICLLGICRCVCTR

[0294] SEQ ID NO: 19 (RC-101 engineered variant): GICRCIOGRG ICRCICGK

[0295] SEQ ID NQ:20 (Sequence 707.2): GICRCICLLGICRCICLL

[0296] SEQ ID NO:21 (Consensus sequence 4, based on specific sequences 704, 708, 705, 712, 715, 716, 717, 709, 710, 711 and 707.2): R C (V / l / L) C (T / R / G / L) (R / L) (G / R) (F / V / l) C R C (V / F / l / L) C (R / T / G / L) (R / L).

[0297] SEQ ID NO:22 (Consensus sequence 5, based on specific sequences 715, 716, 717, 709, 710, 711 and 707.2): (G / R) (F / V / l) C R C (V / l / L) C (T / R / G / L) (R / L) (G / R) (F / V / l) C R C (l / L) C (R / T / G / L) (R / L).

[0298] SEQ ID NO:23 (Consensus sequence 6, based on specific sequences 704, 708, 705, 712 and 707.2): R C (V / l / L) C (T / R / G / L) (R / L) G (F / V / l) C R C (V / F / l / ) C (R / T / L) (R / L) G (V / F) C. ]

Claims

Claims

1. |A cosmetic composition comprising at least one non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:1 to 13, 15 or 20 to 23, or to a variant or derivative thereof.

2. Non-therapeutic use of a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23, or to a variant or derivative thereof, for the preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject.

3. The non-therapeutic use of

2. , wherein the non-therapeutic preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject comprises the non-therapeutic rejuvenation of the skin, the non-therapeutic prevention of skin ageing, the non-therapeutic strengthening of the skin and / or the reinforcement of the barrier function of the skin in a subject, wherein optionally,- the non-therapeutic rejuvenation of the skin is the reduction and / or treatment of the intrinsic and extrinsic signs of skin ageing, and more preferably the intrinsic and extrinsic signs of skin ageing include wrinkles, especially crow feet’s wrinkles, fine lines, discontinuities of the skin, roughness of the skin, skin sagging, skin color, such as skin redness and skin spots, and / or loss of brightness of complexion; or- the strengthening of the skin comprises improving the biomechanical properties of the skin and / or improving the cohesion between the epidermis and the dermis and preferably the biomechanical properties of the skin are skin elasticity, skin tonicity, skin firmness, dermis thickness, dermis density, sebum content, collagen density, improved collagen renewal, more preferably skin elasticity, skin firmness, dermis thickness, dermis density, and sebum content, and / or optionally- the preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject isachieved by the activation of skin cells, the increase of skin cell growth and proliferation and / or the promotion of skin cell migration, wherein preferably the increase of skin cells activation results in the increase of cell motility, the promotion of keratinocyte barrier function, the increase of production of extracellular components and / or the increase of the interactions of epithelial cells with each other, wherein preferably the extracellular components produced by epithelial cells are selected from the group consisting of epithelial matrix polysaccharides and proteoglycans, glycosaminoglycans, laminins, heparin, heparan sulphate (HSGAGs), chondroitin sulphate, dermatan sulphate (CSGAGs), keratan sulphate, hyaluronic acid and combinations thereof.

4. The non-therapeutic use of any one of

2. or

3. , wherein the preservation and / or improvement of the appearance, of the biomechanical properties and / or of the function of the skin in a subject is achieved by increasing expression of at least one fibroblasts and / or keratinocyte gene selected from ACTA2, COL1A1 , COL3A1 , COL5A1 , ELN, FN1 , FBN1 , FBLN5, HAS1 , HAS2, BGN, DCN, SDC1 , COL4A1 , COL4A2, COL6A3, COL7A1 , FGF1 , FGF2, FGF7, VEGFA, VEGFC, CTGF, COMP, EXT2, HS2ST1 , PDPN, THBS1 , B4GALT1 , BMP1 , CCL2, CHST3, CSGALNACT2, IL15RA, LINC00667, PLOD2, TGFB1 , TNC, UST, CDSN, CNFN, IL1 A, IVL, TGM1 , PALLD, COL5A2, P3H1 , EMILIN1 , NID2, IGF1 R, TGFB3, IFIH1 , IL18R1 , CXCL8, CLDN4, EPHB3, ITGB6, SPARC, POSTN, IL6R, IL6ST, EFNB2, OCLN, LAMA3, LAMB3, LAMC2, TIMP2, HBEGF, EREG, FLRT2, ITGA2, ITGA5 ITGA6, DSG2 and / or WNT5A.

5. The non-therapeutic use of any one of

2. to

4. , wherein the TGF[3 inducible gene activation is achieved by activation of TGF[3 pathway on skin cells, preferably on fibroblast and / or keratinocytes.

6. The non-therapeutic use of any one of

2. to

5. , wherein the non-cyclic peptide is used in combination with mu conotoxin CnIIIC of SEQ ID NO: 14, preferably wherein the first amino acid glutamic acid is in the form of pyroglutamic acid (pGlu).

7. The non-therapeutic use according to any one of

2. to

6. , wherein the non-cyclic peptide is use in combination with vitamin C (or a derivative thereof such as ascorbyl glucoside) and / or bakuchiol.

8. A pharmaceutical composition comprising a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous similar or identical to any one of SEQ ID NO:1 to 13,15 or 20 to 23, or to a variant or derivative thereof.

9. A non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO: 1 to 13, 15 or 20 to 23, or to a variant or derivative thereof, or a pharmaceutical composition according to

8. for use in promoting healing in soft and hard tissues and for use as an immunosuppressive agent in a subject in need thereof.

10. The non-cyclic peptide or pharmaceutical composition for use according to

9. , wherein promoting healing in soft and hard tissues consists in preventing, ameliorating and / or treating a disease or disorder selected from wound, preferably a cutaneous wound, optionally a wound is with impaired healing, venous stasis, pressure ulcer, mucositis, fractures and ischemia-reperfusion injuries.

11. The non-cyclic peptide or pharmaceutical composition for use according to

9. , wherein the wound is in a subject treated with corticosteroids, antineoplastic agents and / or radiation and / or in diabetic and / or aged subject.

12. The non-cyclic peptide or pharmaceutical composition for use according to

9. , wherein the immunosuppressive agent is for use in the treatment, amelioration and / or prevention of autoimmune diseases, preferably selected from the group consisting of multiple sclerosis, arthritis and colitis, and for use in the prevention or attenuation of transplants rejection in a subject in need thereof.

13. The cosmetic composition according to

1. , the non-therapeutic use according to any one of

2. to

6. , the pharmaceutical composition according to

8. or the non-cyclic peptide for useaccording to any one of

9. to

12. , wherein the peptide is defined as a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:4, 6, 9 to 13 , 15 or 20, preferably of SEQ ID NO:4, 9 or 11 to 13, or to a variant or derivative thereof, and preferably defined as a non- cyclic peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO: 4, 6, 9 to 13 , 15 or 20, preferably of SEQ ID NO:4, 9 or 11 to 13, or to a variant or derivative thereof.

14. The cosmetic composition according to

1. or

13. , the non- therapeutic use according to any one of

2. to

6. , the pharmaceutical composition according to

8. or the non-cyclic peptide for use according to any one of

9. to

12. , wherein the peptide is defined as a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to SEQ ID NO:9, or to a variant or derivative thereof, and preferably defined as a non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% identical to SEQ ID NO:9, or to a variant or derivative thereof.

15. The cosmetic composition according to

1. ,

13. or

14. , the non-therapeutic use according to any one of

2. to

6. or

14. , the pharmaceutical composition according to

8. or

14. or the non-cyclic peptide for use according to any one of

9. to

12. or

14. , wherein the peptide binds to TGF[3- Receptor 1 (TGFb-R1 ) with a half-maximal receptor binding concentration of from about 5 ng / ml to about 100 ng / ml, preferably from about 20 ng / ml to about 60 ng / ml, more preferably from about 25 ng / ml to about 35 ng / ml and / or to TGF[3-Receptor 2 (TGFb-R2) with a half-maximal receptor binding of from about 200 ng / ml to about 800 ng / ml, preferably from about 400 ng / ml to about 700 ng / ml, more preferably from about 550 ng / ml to about 650 ng / ml.

16. A cosmetic composition according to any one of

1. and

13. to

16. , further comprising at least one cosmetically acceptablecarrier, diluent and / or adjuvant, preferably a cosmetically acceptable carrier selected from liposomes, nanoparticles, microparticles and emulsions.

17. A cosmetic composition according to any one of

1. and

13. to

16. , further comprising at least one cosmetically active agent selected from brightening agents, anti-redness agents, sunscreens and UV organic or inorganic filters, hydrating agents, moisturizers, humectants, exfoliants, anti-wrinkle agents, anti-ageing agents, slimming agents, anti-acne agents, anti-inflammatory agents, antioxidants, radical scavengers, self tanning agents, depilation or shave agents , hair growth moderators, tightening agents, peptides, vitamins and / or myorelaxing agents, wherein preferably the myorelaxing agent is mu conotoxin CnIIIC of SEQ ID NO: 14, preferably wherein the first amino acid glutamic acid is in the form of pyroglutamic acid (pGlu).

18. A cosmetic composition according to any one of

1. and

13. to

17. , wherein the non-cyclic peptide is present in a concentration of about 0.01 pM to about 10 pM, preferably about 0.05 pM to about 5 pM, more preferably about 0.1 pM to about 2.5 pM, most preferably about 0.2 pM to about 1 pM.

19. A cosmetic composition according to any one of

1. and

12. to

17. , wherein the cosmetic composition further comprises vitamin C (or a derivative thereof such as ascorbyl glucoside) and / or bakuchiol. ]

20. A non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% homologous, similar or identical to any one of SEQ ID NO:3 to 7, 20 or 23, or to a variant or derivative thereof.

21. A non-cyclic peptide having a sequence comprising an amino acid sequence at least 85% identical to any one of SEQ ID NO:3 to 7, 20 or 23, or to a variant and / or derivative thereof for use as a medicament. ]

Images