Cosmetic hyaluronic acid binding peptides

Abstract

Synthetic peptides capable of replicating hyaluronic acid (HA) receptors, including the receptor for HA-mediated motility (RHAMM), and other HA receptor binding properties, with multiple overlaying or non-overlaying binding domains. These peptides provide better binding than endogenously expressed peptides and are also able to polymerize with high fragments of HA to form a macromolecular gel. Further, in some embodiments, a dermal / transdermal delivery component may be added to these novel synthetic peptides, separated with a cleavage site that may be cleaved through a variety of mechanisms, thus separating the peptide from the dermal / transdermal delivery component.

Description

Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025COSMETIC HYALURONIC ACID BINDING PEPTIDESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application No. 63 / 703,438 filed October 4, 2024, the specification of which is incorporated herein in its entirety by reference.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (ARIZ_24.31_PCT_Sequence_Listing_10.3.25.xml; Size: 11,646 bytes; and Date of Creation: October 3, 2025) is herein incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0003] The key molecule associated with aging skin is hyaluronic acid (HA) expression through HAS-1 and HAS-2, which allows skin to retain its resilience, turgor, and flexibility due to water absorption. Although HA can be added to the skin exogenously, it has little effect on reducing major signs of aging. This is largely due to the loss of HA keratinocytes receptors called hyaladherins. The receptor for HA-mediated motility (RHAMM) is one of the major receptors, and its loss over time, along with other hyaladherins (e.g., CD44), is considered to be one of the major causes of skin aging.FIELD OF THE INVENTION

[0004] The present invention relates to the field of skin-enhancing peptides, including cosmetic synthetic skin-enhancing peptides, especially those related to HA.BRIEF SUMMARY OF THE INVENTION

[0005] It is an objective of the present invention to provide compositions that allow for the supplementation, enhancement, or replacement of proteins related to HA, as specified in the independent claims. Embodiments of the invention are given in the dependent claims. Embodiments of the present invention can be freely combined with each other if they are not mutually exclusive.

[0006] The present invention is directed towards synthetic peptides (17x-3, BHP4, Peptide 4, and others) capable of replicating RHAMM and other HA receptor binding properties with multiple overlaying binding domains, including said synthetic peptides as part of a "skin-enhancing compound" (as defined herein) and also including computer-assisted methods for automaticallyReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 generating said peptide sequences. These peptides are 2-4-fold better binders than endogenously expressed peptides and are also able to polymerize with high fragments of HA to form a macromolecular gel. Further, in some embodiments, a dermal / transdermal delivery component may be added to these novel synthetic peptides. In some embodiments, a polyethylene glycol (PEG) group (in some embodiments, a PEG group of 3.5-10 kDa) may be added to the peptide, separated with a cleavage site that may be cleaved from the peptides through a variety of mechanisms. In some embodiments, the cleavage site may comprise a matrix metalloproteinase (MMP) cleavage site, or another cleavage site for other proteases involved in collagen reorganization. In some embodiments, the peptide (e.g., RHAMM-replicating peptide), dermal / transdermal delivery component (e.g., PEG), and cleavage site may together comprise the “skin-enhancing compound.”

[0007] Without wishing to limit the present invention to any theory or mechanism, it is believed that the compositions described herein are beneficial over prior art approaches for at least three reasons. First, PEG will inhibit the peptide(s) polymerization with HA (and thus will inhibit self-assembly). Second, dermal fibroblasts, keratinocytes, and macrophages actively secrete MMP and will cleave PEG away, allowing for gel polymerization only at the cell interface and / or extracellular matrix. Third, PEG is an FDA approved dermal / transdermal molecule that will allow the peptide to enter the skin and contact cells, by passing through the epidermal layers and into the dermal layers of the skin. This effectively generates a ‘pro-drug’ style HA gel that substitutes lost RHAMM / CD44 with a gel at the cell interface, capable of being applied to the skin topically in a water-soluble solution at higher concentrations with HA and other cosmetic products (self-assembly would otherwise typically inhibit this). Further, photo-cleavable cleavage sites, including in some embodiments photo-cleavable amino acids, such as 3-amino-3-(2-nitrophenyl)-propionyl (ANP), can be substituted instead of the MMP substrate to generate a UV-sensitive gel that is capable of forming with sun exposure or exposure to other sources of UV light. This allows for the use of sunscreens and lotions to boost HA integrity with other UV protecting agents. In some embodiments, photo-cleavable cleavage sites include 3-amino-3-(2-nitrophenyl)-propionyl (ANP) and other such photo-cleavable cleavage sites, including those in FIGs. 6A-6B. Tunable parameters of the present invention include PEG length (without wishing to limit the present invention to any particular theory or mechanism, it is believed that a PEG of 3.5-10 kDa is ideal because it is large enough to inhibit self-assembly of the peptides, but not so large that it prevents penetration of skin layers), MMP type and substratesReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025(comprising hundreds of combinations with extensive specificities), HA peptides (which, in some embodiments, may have various binding affinities), and the use of various photolabile linkers, including those that can be applied via solid phase synthesis, allowing for a variety of photokinetic properties.

[0008] Some of the unique and inventive technical features of the present invention are novel synthetic peptide sequences capable of replicating RHAMM and other proteins with similar function, the inclusion of dermal / transdermal delivery components to these peptides, and the inclusion of a cleavage site capable of separating the RHAMM-replicating peptide from the dermal / transdermal delivery component, thereby allowing the RHAMM-replicating peptide to associate with a cell membrane surrounding HA and / or HA surrounding a cell membrane. In some embodiments, the present invention may also include a chelate label, including tetraxetan (DOTA), diethylenetriamene pentaacetate (DPTA) , pyridylmethyl amines (MPA / DPA / TPA), Iminodiacetic acid (IDA), porphyrins, and copper / manganese tripeptides. Without wishing to limit the invention to any theory or mechanism, it is believed that the technical feature of the present invention advantageously provides for dermal / transdermal delivery of RHAMM-replicating peptides and / or HA binding / polymerization peptides, which allows for the supplementation, enhancement, or replacement of proteins related to HA, including RHAMM-replicating peptides and / or HA binding / polymerization peptides, thereby alleviating or reversing skin aging associated with reductions in the content of HA and downregulation of HAS-1, HAS-2, CD44 and RHAMM, which are normally associated with the skin aging process.

[0009] Furthermore, without wishing to limit the present invention to any particular theory or mechanism, it is believed that RHAMM-replicating peptides, when used alone, cannot be formulated at the concentrations required for topical application because they spontaneously self-assemble with hyaluronic acid before penetrating the skin. While PEGylation of peptides is known in the art, PEGylation alone simply inhibits the binding activity of these peptides, which, while preventing self-assembly, also inhibits their ability to bind HA and thus exert their beneficial effects. In the present invention, RHAMM-replicating peptides are conjugated with a delivery component (e.g., PEG) via a cleavage site, such that the delivery component prevents premature self-assembly during formulation and epidermal transit, but is then removed by local triggers (e.g., MMP secretion in the dermis or UV exposure) to restore HA-binding activity. This approach solves a long-standing problem and unmet need: how to deliver HA-binding peptides at high concentrations through the epidermis without losing function. The use of a cleavableReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 delivery component in this way, with a site-specific cleavage site to convert the peptide into a functional “pro-drug” style gel at the cell interface, is not taught or suggested in the prior art. Furthermore, the development of this portion of the present invention required extensive experimentation, because the delivery component (e.g., PEG) chain length, cleavage conditions, and peptide design all must be “balanced” to function together properly.

[0010] The peptides contain B(X7)B binding domains that present as diagonals, represented by the formula Bl + 8 = B2, on a helical net, where Bl and B2 are positively charged residues (e.g., Lys or Arg). These domains can be either contiguous (contain the same positively charged residue) or non-contiguous (do not contain the same positively charged residue). The X7 region of the B(X7)B binding domains may or may not contain one or more positively charged residues. Additionally, every diagonal adjacent to a diagonal containing B(X7)B binding domains does not contain any B(X7)B binding domains and is composed of a mixture of hydrophobic residues (e.g. Ala, Vai, Leu, He, Phe, Tyr or Trp) and polar residues (e.g., Ser, Thr or Asn, Gin) or a His residue. The present invention also features a computer-assisted method for automatically generating peptide sequences containing BX7B domains, each peptide sequence configured to bind to hyaluronic acid. Without wishing to limit the present invention to any particular theory or mechanism, it is believed that this aspect of the present invention provides more robust constraints than simply outputting sequences for RHAMM-based hyaluronan binders.[OH] None of the presently known prior references or work has the unique inventive technical feature of the present invention. Furthermore, the inventive technical features of the present invention contributed to a surprising result. For example, the present invention allows for the alleviation or reversal of skin aging processes associated with reductions in the content of HA and downregulation of HAS-1, HAS-2, CD44, and RHAMM, which has not been previously possible.

[0012] Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0013] The features and advantages of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:

[0014] FIG. 1 shows a schematic representation of an embodiment of the present invention, including a skin-enhancing compound, said skin-enhancing compound comprising a RHAMM-replicating peptide (17x-3 in this embodiment; SEQ ID NO: 3), a dermal / transdermal delivery component (PEG3500 in this embodiment); a cleavage site (e.g., SEQ ID NO: 12) linking the RHAMM-replicating peptide and the dermal / transdermal delivery component (an MMP-2 cleavage site in this embodiment), and a chelate label (DOTA in this embodiment).

[0015] FIG. 2 shows hydrophobic moments of peptides of the present invention as presented by helical wheels. mPEP35 corresponds to SEQ ID NO: 1.; 17x3 corresponds to SEQ ID NO: 3.; Peptide #4 corresponds to SEQ ID NO: 4.; BHP3 corresponds to SEQ ID NO: 5.; and BHP4 corresponds to SEQ ID NO: 6.

[0016] FIG. 3 shows AX9 series of amphipathic a-helices exhibiting a hydrophobic face encased by the two grey lines (including a grey shading) on the helical net.

[0017] FIG. 4 shows Multi-Faceted Peptide Design to Balance BX7B Hyaluronic Acid (HA) Binding Domains per Face. F peptides are optimized or rebalanced BX7B domains to distribute HA binding among the helical faces as evenly as possible. It is believed that multiple BX7B per faces can cause a competitive binding event that may be deleterious, and that more singular BX7B domains per face could result in more robust binding. 1-scrm corresponds to SEQ ID NO: 2.; mPep35 corresponds to SEQ ID NO: 1.; 17x-3 corresponds to SEQ ID NO: 3.; 17x-3-F corresponds to SEQ ID NO: 9.; Peptide 4 corresponds to SEQ ID NO: 4.; Peptide 4-F corresponds to SEQ ID NO: 10.; BHP-4 corresponds to SEQ ID NO: 6.; and BHP-4-F corresponds to SEQ ID NO: 11.

[0018] FIG. 5 shows the results of a binding assay of peptides on 1 mg / ml HA in 0.1 ml coatings. Peptides were treated 24 hours in phosphate buffered saline (pH 7.4), and labelled with biotin targeting Alexafluor 488-streptavidin. 17x-3 and 17x-3-F are comparable binders, while 4-F and BHP-4-F are better binders are 1.25-2.5 mg / ml than their original designs, but not at higher concentrations. Redistributing and optimizing BX7B to faces resulted in more robust binders and lower doses, but may reach a ceiling effect in binding at higher concentrations. Displayed left to right in the bar graph, for each peptide, are results obtained for 0 mg / ml, 1.25 mg / ml, 2.5 mg / ml,Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 20255 mg / ml, and 10 mg / ml.

[0019] FIG. 6A-6B shows linkers, or cleavage sites, that may be used to link the RHAMM-replicating peptide and the delivery component (e.g., dermal or transdermal delivery component). FIG. 6A shows o-Nitrobenzyl linkers, and o-Nitroveratryl linkers. FIG. 6B shows phenacyl linkers, benzoin linkers, pivaloyl linkers, and other photolabile linkers.

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] As used herein, the term “BX7B domain” refers to a domain found in some HA-binding proteins, which serves as an HA-binding site, in which B represents a basic amino-acid residue and X represents any nonacidic residue.

[0022] As used herein, the term "skin-enhancing compound" may refer to a peptide (e.g., RHAMM-replicating peptide) as bound to a dermal / transdermal delivery component (e.g., PEG) via a cleavage site or linker.

[0023] As used herein, the term “skin-enhancing cosmetic composition” may refer to a composition comprising at least one skin-enhancing compound, and at least one other component (for example, HA).

[0024] As used herein, the term “RHAMM-replicating peptide” means a peptide capable of replicating the hyaluronan-binding properties of RHAMM and related hyaladherins (e.g., CD44).

[0025] As used herein, the term "peptide" refers to a short polymer of amino acids linked together by peptide bonds. In contrast to other amino acid polymers (e.g., proteins, polypeptides, etc.), peptides are typically of about 50 amino acids or less in length. A peptide may comprise natural amino acids, non-natural amino acids, amino acid analogues, and / or modified amino acids. A peptide may be a subsequence of naturally occurring protein or a non-natural (synthetic) sequence.

[0026] The terms "peptide mimetic" or "peptidomimetic" refer to a peptide-like molecule that emulates a sequence derived from a protein or peptide. They are compounds whose essential elements (pharmacophore) mimic a natural peptide in 3D space and which retain the ability to interact with the biological target and produce the same biological effect.

[0027] A peptide mimetic or peptidomimetic may contain amino acids and / or non-amino acid components. Examples of peptidomimetics include chemically modified peptides, peptoids (side chains are appended to the nitrogen atom of the peptide backbone, rather than to the a-carbons), P -peptides (amino group bonded to the P carbon rather than the a carbon), etc.

[0028] As used herein, a “conservative” amino acid substitution refers to the substitution of anReference No.: ARIZ 24.31 PCTInventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 amino acid in a peptide or polypeptide with another amino acid having similar chemical properties, such as size, charge, polarity, etc.. For purposes of the present disclosure, each of the following eight groups contains amino acids that are conservative substitutions for one another: (1) Alanine (A) and Glycine (G); (2) Aspartic acid (D) and Glutamic acid (E); (3) Asparagine (N) and Glutamine (Q); (4) Arginine (R) and Lysine (K); (5) Isoleucine (I), Leucine (L), Methionine (M), and Valine (V); (6) Phenylalanine (F), Tyrosine (Y), and Tryptophan (W); (7) Serine (S) and Threonine (T); and (8) Cysteine (C) and Methionine (M).

[0029] Naturally occurring residues may be divided into classes based on common side chain properties, for example: polar (hydrophilic) positive (histidine (H), lysine (K), and arginine (R)); polar (hydrophilic) negative (aspartic acid (D), glutamic acid (E)); polar (hydrophilic) neutral (serine (S), threonine (T), asparagine (N), glutamine (Q)); non-polar (hydrophobic) aliphatic (alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M)); non-polar (hydrophobic) aromatic (phenylalanine (F), tyrosine (Y), tryptophan (W)); proline and glycine; and cysteine. As used herein, a “semi-conservative” amino acid substitution refers to the substitution of an amino acid in a peptide or polypeptide with another amino acid within the same class.

[0030] In some embodiments, unless otherwise specified, a conservative or semi-conservative amino acid substitution may also encompass non-naturally occurring amino acid residues that have similar chemical properties to the natural residue. These non-natural residues are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include, but are not limited to, peptidomimetics and other reversed or inverted forms of amino acid moieties. Embodiments herein may, in some embodiments, be limited to natural amino acids, non-natural amino acids, and / or amino acid analogs. Non-conservative substitutions may involve the exchange of a member of one class for a member from another class.

[0031] Non-limiting examples of conservative substitutions are as follows: the aromatic Tyrosine may be conservatively substituted with aromatic phenylalanine, or basic Arginine may be conservatively substituted with basic Lysine. Table 1A and IB show non-limiting examples of conservative amino acid substitutions.

[0032] Table 1A and IB:Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025

[0033] As used herein, the term “sequence identity” refers to the degree to which two polymer sequences (e.g., peptide, polypeptide, nucleic acid, etc.) have the same sequential composition of monomer subunits. The term “sequence similarity” refers to the degree with which two polymer sequences (e.g., peptide, polypeptide, nucleic acid, etc.) differ only by conservative and / or semi-conservative amino acid substitutions. The “percent sequence identity” (or “percent sequence similarity”) is calculated by: (1) comparing two optimally aligned sequences over a window of comparison (e.g., the length of the longer sequence, the length of the shorter sequence, a specified window, etc.), (2) determining the number of positions containing identical (or similar) monomers (e.g., same amino acids occurs in both sequences, similar amino acid occurs in both sequences) to yield the number of matched positions, (3) dividing the number of matched positions by the total number of positions in the comparison window (e.g., the length of the longer sequence, the length of the shorter sequence, a specified window), and (4) multiplying the result by 100 to yield the percent sequence identity or percent sequence similarity. For example, if peptides A and B are both 20 amino acids in length and have identical amino acids at all but 1 position, then peptide A and peptide B have 95% sequence identity. If the amino acids at the non-identical position shared the same biophysical characteristics (e.g., both were acidic), then peptide A and peptide B would have 100% sequence similarity. As another example, if peptide C is 20 amino acids in length and peptide D is 15 amino acids in length, and 14 out of 15Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 amino acids in peptide D are identical to those of a portion of peptide C, then peptides C and D have 70% sequence identity, but peptide D has 93.3% sequence identity to an optimal comparison window of peptide C. For the purpose of calculating “percent sequence identity” (or “percent sequence similarity”) herein, any gaps in aligned sequences are treated as mismatches at that position.

[0034] As used herein, the term “natural amino acids” refers to the twenty amino acids that are found in nature, i.e., occur naturally. The natural amino acids are as follows: alanine, arginine, glycine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, serine, threonine, histidine, lysine, methionine, proline, valine, isoleucine, leucine, tyrosine, tryptophan, and phenylalanine. This application adheres to the IUPAC rules of standard abbreviations for amino acids.

[0035] Each amino acid may be either natural or unnatural of the "D" or "L" configuration which corresponds to the stereochemical designation "S" and "R," respectively, as defined in the RS system of Cahn et al., (Pure Applied Chemistry, 45: 11-30 (1974), and references cited therein). As known to one of ordinary skill in the art, only L-amino acids are manufactured in cells and incorporated into proteins. As used herein, the letter "D" preceding any three-letter abbreviation for an amino acid, e.g., as in "D-Phe," denotes the D-form of the amino acid, and a lack thereof refers to the L-form.

[0036] As used herein, the term “unnatural amino acids” refers to amino acids that are not naturally encoded or found in the genetic code of any organism. Typically, the unnatural amino acids are different from the twenty naturally occurring amino acids in their side chain functionality. Non-limiting examples of unnatural amino acids include 2-Naphthylalanine (Nal(2’)), Norleucine (Nle), and Pipecolic acid (Pip).

[0037] The peptides described herein may be cyclized through bridging of the residues via ring closing reactions. As used herein, cyclization is denoted by “c” or “cyclo.” In some embodiments, the side chain of a residue is linked to the side chain of another residue via a linker. In some embodiments, the linker LI is a carba, lactam, disulfide, thioether, or succinic linker. As understood by one of ordinary skill in the art, the linker is not limited to the aforementioned examples and may depend upon the specific cyclization chemistry used to produce the cyclic peptide. As a non-limiting example, residues can be linked via an amide bond formation reaction, which may form a -(CH2)-CO-NH-(CH2)n- bridge, where n=l,2,3,4. In addition, carbon-carbon bonds, lactone, thioether, ether, disulfide, and other covalent bonds can be used as a part of the ring closing reactions. Without wishing to limit the invention to a particular theory or mechanism, the type of linker can affect the structural, chemical, andReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 biological activity of the peptide ligand.

[0038] As defined herein, a P-amino acid or P-peptide refers to an amino acid in which the amino group of -NH2 is attached to the secondary carbon rather than the a carbon. For example, a methylene group (CH2) is inserted into the side chain at the beta position of that side chain. The flexibility to generate a vast range of stereo- and regioisomers, together with the possibility of di substitution, significantly expands the structural diversity of P-amino acids. For instance, the incorporation of P-amino acids has been successful in creating peptidomimetics that not only have potent biological activity, but are also resistant to proteolysis.

[0039] Referring now to FIGs. 1-6B, the present invention features a skin-enhancing compound comprising: a RHAMM-repli eating peptide, a delivery component, and a cleavage site linking the RHAMM-replicating peptide and the delivery component. In some embodiments, protein-mediated cleavage of the cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid. Without wishing to limit the present invention to any particular theory or mechanism, it is believed that the use of a delivery component is advantageous in that it prevents premature polymerization of the RHAMM-replicating peptides, while also allowing for improved penetration of skin layers.

[0040] In other embodiments, the present invention features a skin-enhancing cosmetic composition comprising: hyaluronic acid and one or more skin-enhancing compounds, each comprising: a RHAMM-replicating peptide, a delivery component, and a cleavage site linking the RHAMM-replicating peptide and the delivery component. In some embodiments, protein-mediated cleavage of the cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid. In some embodiments, the RHAMM-replicating peptide polymerizes with the hyaluronic acid upon cleavage of the delivery component to form a macromolecular gel. In some embodiments, protein-mediated cleavage of the cleavage site may be accomplished by a matrix metalloproteinase (MMP), or another protease, especially those involved in collagen reorganization. In some embodiments, dermal fibroblasts, keratinocytes, and macrophages actively secrete MMP, allowing for gel polymerization only at the cell interface and / or extracellular matrix. In some embodiments, protein-mediated cleavage may be accomplished by ADAM (a disintegrin and metalloproteinase) or ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), meprins, neprilysin, an aminopeptidase, a carboxypeptidase, furin, a proprotein convertase, cathepsins, or any other appropriate protease.Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025

[0041] In still other embodiments, the present invention features a skin-enhancing compound comprising: a RHAMM-repli eating peptide, a delivery component, and a photo-cleavable cleavage site linking the RHAMM-replicating peptide and the delivery component. In some embodiments, ultraviolet-mediated cleavage of the photo-cleavable cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid. Ultraviolet-mediated cleavage may allow the skin-enhancing compounds of the present invention to be included in sunscreens or similar topical formulations, thereby allowing activation of the RHAMM-replicating peptide upon sun or other ultraviolet light exposure.

[0042] In some embodiments, the present invention features a skin-enhancing cosmetic composition comprising: hyaluronic acid; and one or more skin-enhancing compounds, each comprising: a RHAMM-replicating peptide, a delivery component, and a photo-cleavable cleavage site linking the RHAMM-replicating peptide and the delivery component. In these embodiments, ultraviolet-mediated cleavage of the photo-cleavable cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid. The RHAMM-replicating peptide is thereby able to polymerize with the hyaluronic acid to form a macromolecular gel.

[0043] In some embodiments, the delivery component is a dermal delivery component or a transdermal delivery component. In some embodiments, the delivery component comprises PEG 200, PEG 300, PEG 400, PEG 600, PEG 900, PEG 1000, PEG 1450, PEG 1540, PEG 2000, PEG 3000, PEG3350, PEG 4000, PEG 4600, or PEG 8000. Without wishing to limit the present invention to any particular theory or mechanism, it is believed that a PEG of 3.5-10 kDa is ideal for most topical applications because it is large enough to inhibit self-assembly of the peptides, but not so large that it prevents penetration of skin layers. In some embodiments, the PEG3350 has a molecular weight of between about 3015 and 3685. In other embodiments, the delivery component comprises polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), chitosan, sodium alginate, a phospholipid or fatty acid, squalene and / or squalane, ceramides, PLGA (Poly(lactic-co-glycolic acid)), polylactic acid (PLA), polycaprolactone (PCL), or the like.

[0044] In some embodiments, the cleavage site comprises a matrix metalloproteinase cleavage site. In some embodiments having a photo-cleavable cleavage site, the photo-cleavable cleavage site comprises an o-nitrobenzyl linker, o-Nitrobenzyl linker, an o-nitroveratryl linker, a phenacyl linker, a benzoin linker, or a pivaloyl linker (FIG. 6A and 6B).Reference No.: ARIZ 24.31 PCTInventor’s last name: Koss et al.Document Date: 10 / 6 / 2025

[0045] In some embodiments, the RHAMM-replicating peptide comprises: 17x-3, BHP4, or Peptide 4. In some embodiments, the RHAMM-replicating peptide comprises a sequence according to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11.

[0046] In other embodiments, the present invention features a computer-assisted method for automatically generating peptide sequences containing BX7B domains, each peptide sequence configured to bind to hyaluronic acid. In some embodiments, the B(X7)B domains are positionally located as they are described in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, where the hydrophobicity ratio is altered. Table 2 shows a list of peptide and amino acid sequences that comprise some embodiments of the RHAMM-replicating peptide of the present invention, as well as other sequences related to the invention (namely, SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 12, the identities of which are notated in the right-most column of Table 2), as shown as linear sequences.

[0047] Table 2: Peptide and Amino Acid SequencesReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025

[0048] In some embodiments, the computer-assisted method further comprising randomly generating one or more peptide sequences, each peptide sequence having a length of at least fourteen or fifteen positions, each position comprising a residue, wherein each peptide sequence conforms to at least one of the following parameters: a) wherein each peptide sequence of the one or more peptide sequences comprises a first K residue in a first position and a second K residue in a ninth position; b) wherein each peptide sequence of the one or more peptide sequences comprises an L residue, an M residue, a Q residue, an I residue, an F residue, an A residue, a Y residue, or a T residue in an eighth position, an eleventh position, a twelfth position, a fifteenth position, an eighteenth position, a nineteenth position, a twenty-second position, a twenty-fifth position, and a twenty-sixth position; or c) wherein each peptide sequence of the one or more peptide sequences comprises an N residue, an S residue, a V residue, or a Y residue in a second position and a twenty-ninth position.

[0049] In some embodiments, the computer-assisted method further comprises introducing additional B1(X7)B2 domains, said B1(X7)B2 domains having positive charges, thereby increasing interactions between hyaluronic acid and a peptide having the automatically generated peptide sequence. In certain embodiments, each peptide sequence of the one or more peptide sequences that is generated with computer assistance comprises consecutive non-polar residues only at a tenth position and the eleventh position, a seventeenth position and the eighteenth position, and a twenty -fourth position and the twenty -fifth position.

[0050] In some embodiments, the computer-assisted method further comprises validating a peptide sequence generated by the computer-assisted method by predicting a 3-dimensional structure of the peptide sequence. In other embodiments, the computer-assisted method further comprises simulating molecular docking between a peptide sequence generated by the computer-assisted method and hyaluronic acid. In still other embodiments, the computer-assisted method further comprises determining one or more binding affinities, one or more molecular interactions between the peptide sequence and hyaluronic acid, or a combination thereof. In some embodiments, the molecular interactions comprise at least one of electrostatic interactions, hydrogen bonding, hydrophobic interactions, TI- TI interactions, cation-7t interactions, Van der Waals interactions, or water-mediated interactions.

[0051] In some embodiments, the computer-assisted method further comprises determining if a peptide sequence generated by the computer-assisted method is described in a patent application or patent, wherein determining comprises querying a computer-mediated patent database with the peptide sequence and validating the peptide sequence if no matches are found in theReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 computer-mediated patent database.

[0052] In some embodiments, the present invention features a composition comprising a skin-enhancing compound and hyaluronic acid.

[0053] In some embodiments, the present invention features a method of enhancing at least one of the hydration, texture, healing, or elasticity of skin, the method comprising administering a composition comprising a skin-enhancing compound. In some embodiments, the composition comprises both a skin-enhancing compound and hyaluronic acid.

[0054] The present invention features a computer-assisted method for automatically generating peptide sequences containing BX7B domains. In some embodiments, the computer-assisted method can comprise randomly generating one or more peptide sequences. In some embodiments, each peptide sequence has a length of at least fourteen positions. Each position of the two or more positions may comprise a residue comprising one of the 19 common amino acids, but is not limited to those amino acids. In some embodiments, each position of the two or more positions may comprise a residue comprising a positively-charged residue, and / or may comprise ornithine (e.g., L-Ornithine), 2,4-diaminobutyric acid (Dab), 2,3 -diaminopropionic acid (Dap), physiological amino acids citrulline and alpha-aminobutyric acid, and other amino acids, including but not limited to non-proteinogenic amino acids, including but not limited to L-a-Amino-n-butyric acid, 'y-Amino-n-butyric acid, DL-P-Aminoisobutyric acid, L-2-aminoisobutyric acid, L-citrulline, phenylglycine, homocysteine, alpha-aminobutyric acid, 5-hydroxylysine, hydroxy-L-proline, 1-methyl-L-histidine, 3-methyl-L-histidine, sarcosine, taurine, and / or the like. In some embodiments, Pro, Asp, and Glu are excluded. In some embodiments, Asp and Glu are excluded. In some embodiments, the peptide sequence has a length of 27 or more positions containing four to six B1(X7)B2 binding domains. In some embodiments, the peptide sequence has a length of 27 or fewer positions containing four to six B1(X7)B2 binding domains. In some embodiments, the peptide sequence has a length of 24-30 residues. In some embodiments, each peptide sequence of the one or more peptide sequences comprises a K or R or positively charged residue starting at position number one, two, three, or four (Bl) and a second K residue at a position designated by the following formula: Bl + 8 = B2, where B2 is the second K or R or positively charged residue, thus comprising a B1(X7)B2 HA binding domain. The X7 residues comprise the 20 common amino acids, physiological, and / or unnatural / non-proteinogenic amino acids. In some embodiments, these amino acids exclude Pro, Asp, and Glu. In some embodiments, these amino acids exclude Asp and Glu. In some embodiments, each peptide sequence will contain either contiguous (each HA binding domainReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 shares a common positively-charged residue) or non-contiguous (each HA binding domain does not share a common positively charged residue) portions, such that there would be at least five HA binding domains in the entire length of the peptide. In some embodiments, the computer-assisted method for automatically generating peptide sequences allows for flexibly applying the above stated rules for generating peptide sequences, thus, expanding the types of other HA binding sequences that may be generated.

[0055] In some embodiments, the HA binding domains of the peptide sequences generated by the program are developed from three independent known sequences known to code for HA binding domains, and each of these sequences are used to generate peptides that have the same HA binding domains, but may vary in their hydrophobicity / hydrophilicity ratio (based on the scale of Monera, Sereda et al.), which results in peptides with varying non-polar / polar characteristics. In some embodiments, each of the three independent programs are constituents of a larger program, where each of the three individual programs are run independently of the other two programs or any two or three programs are run as one unit, which utilizes an Al approach to develop new peptide sequences with better HA binding characteristics. In some embodiments, the HA binding domains will lie on a specific diagonal of a helical net and adjacent diagonals do not contain HA binding domains. In some embodiments, the helical net diagonals that do not contain HA binding domains are composed of amino acids randomly chosen from the following groups of amino acids: non-polar amino acids (Phe, Tyr, Ala, Leu, He, Vai, Trp, or Met) or polar amino acids (Ser, Thr, Asn, Gin) or physiological or unnatural / non-proteinogenic amino acids. In some embodiments, the program contains general rules including but not limited to residue type / placement in the sequence, e.g., small polar amino acids (Ser, Asn) near the C- or N-terminal ends of the sequence and large polar residues (Thr, Gin) near the center of the sequence.

[0056] The present invention features a computer-assisted method for automatically generating peptide sequences containing BX7B domains. In some embodiments, the computer-assisted method may comprise randomly generating one or more peptide sequences. Each peptide sequence may have a length of at least 14 positions. Each position of the at least 14 positions may comprise a residue. In some embodiments, each peptide sequence of the one or more peptide sequences comprises a first K residue in a first position and a second K residue in a ninth position. In some embodiments, each peptide sequence of the one or more peptide sequences comprises an L residue, an M residue, a Q residue, an I residue, an F residue, an A residue, a YReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 residue, or a T residue in an eighth position, an eleventh position, a twelfth position, a fifteenth position, an eighteenth position, a nineteenth position, a twenty-second position, a twenty-fifth position, and a twenty-sixth position. In some embodiments, each peptide sequence of the one or more peptide sequences comprises an N residue, an S residue, a V residue, or a Y residue in a second position and a twenty-ninth position. In some embodiments, each peptide sequence of the one or more peptide sequences comprises consecutive non-polar residues only at a tenth position and the eleventh position, a seventeenth position and the eighteenth position, and a twenty-fourth position and the twenty-fifth position. In some embodiments, there may be no consecutive non-polar residues at any position in the peptide sequence other than at positions 10 and 11, positions 17 and 18, and positions 24 and 25. Without wishing to limit the present invention to any particular theory or mechanism, it is believed that the automatically generated peptide sequences containing BX7B domains should be at least 14 residues in length. A theoretical minimum is 9 residues (as this represents a single BX7B motif). However, peptides with optimal activity may be in the range of 18-35 residues. Since there are seven possible faces for a helix and there are 3.6 residues per turn, there would be 25 residues in approximately seven helical turns. For this reason, in some embodiments, peptides approximately 25 residues in length may be optimal for some applications. In other embodiments, peptides with 18 residues (5 turns) may have five binding domains, and may be optimal for other applications. Thus, each face of such a peptide would have a binding domain. However, the ideal peptide length may vary. For example, peptide BHP4 has only four binding domains, but was experimentally found to have nearly ideal properties. Because peptides having four binding domains were thus found to have desirable characteristics, and there are 3.6 residues per turn, a peptide with roughly 14-15 peptide residues would be expected to, in some embodiments, have ideal or near ideal properties. However, other peptides experimentally found to have desirable properties had a greater number of residues, for example, Peptide 17x-3 has desirable properties and is 27 residues in length. Therefore, the ideal peptide length may vary.

[0057] Referring now to FIG. 3, FIG. 3 shows AX9 series of amphipathic a-helices (note: peptides having AX9 series of a-helices may be referred to as simply “AX9 Peptides,” “Peptide AX9,” or the like, and which are discussed in greater detail below) exhibiting a hydrophobic face encased by the two grey lines (including a grey shading) on the helical net. The hydrophobic face is composed of three adjacent 7-residue diagonals, i.e., (A6, A13), (A2, X9-guest residue, A16) and (A5, A12), where a 7-residue diagonal is defined by the formula residue #l+7=residue #2 inReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 the linear sequence. Position AX9 is in the center of the hydrophobic face. The residue markers coloured grey, Ala, are in the hydrophobic face and the blue (Lys or Arg) and red (Glu) are in the hydrophilic face of the peptide. The AX7 series of amphipathic a-helices (note: peptides having AX7 series of a-helices may be referred to as simply “AX7 Peptides,” “Peptide AX7,” or the like, and which are discussed in greater detail below) exhibiting a hydrophilic face encased by the two grey lines (including grey shading) on the helical net. The hydrophilic face is composed of four adjacent 7-residue diagonals, i.e., (El, E8, E15), (K4, Kll, K18), (X7-guest residue, K14) and (E3, E10, E17). Position AX7 is surrounded by hydrophilic residues, Glu & Lys. Representative helical wheels and models are shown with highlighted faces.

[0058] In some embodiments, two engineering perspectives may be used to approach the design of new peptide sequences containing Bl (X7)B2 domains, including new HA binders, specifically (i) valency, i.e., increased number of positive charges by introducing additional B1(X7)B2 domains for increased interaction with HA, and (ii) analysing the multifaceted characteristic of a peptide with a low degree of amphipathicity (alternatively stated, a low <pH>).

[0059] Regarding (i), with respect to HA binding domains, i.e., B 1(X7)B2, positive charges in the center of the X7region (position #4) adjacent to the B2 residue (position #7) or clustered within the X7region will enhance the binding of a peptide to HA. Thus, a positive charge in the center of the X7region, designated as [4R7], or flanking the B2 residue, designated as [7R7], should enhance binding to HA.

[0060] Regarding (ii), Peptide AX9 (FIG. 3) was used to define what constitutes a hydrophobic helical face. The hydrophobic face consists of six Ala residues centered by a “guest residue” in the middle of the hydrophobic face. The primary amino acid sequence for a hydrophobic face is based on a 3-1-3; 3-1-3 repeat. For example, starting with residue 2: 2 + (3) = 5, 5 + (1) = 6, 6 + (3) = 9; 9 + (3) = 12, 12 + (1) = 13. 13 + (3) = 16; thus, hydrophobic residues are placed at position numbers 2, 5, 6, 9 (guest residue), 12, 13 and 16 in the primary sequence. This mathematical formula will allow one to determine the placement of hydrophobic residues in the primary sequence, which will present as a hydrophobic face. Each position in the helical net will define a specific helical diagonal. These diagonals have been termed a 7-residue diagonal, based on the following formula: residue #1 + 7 = residue #2, in order to distinguish it from the HA binding diagonals defined by Bl + 8 = B2. Furthermore, this arrangement defines a face that will present residues Bl and B2 (of B1(X7)B2) on the same “side” of the a-helix and those twoReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 residues will be on a specific 7-residue diagonal. This is depicted on the helical net by drawing two solid lines enclosing the residues within a helical face. Note: the “7” in the above formula represents the displacement between the first and second residue in the linear sequence, not the number of amino acids in the helical face. A more specific description of helical net diagonals is: Residues A6 and Al 3 define a diagonal (Note: 13 - 6 = 7), A2, X9, Al 6 define a second diagonal, and A5 and A12 define a third diagonal. Thus, any diagonal consisting of residues displaced by seven residues will define the position in the primary sequence of the next residue in that diagonal. Any such three adjacent diagonals will define a hydrophobic face on an a-helix. In reference to peptide AX9, all the residues to the left of the left-hand line and to the right of the right-hand line will then constitute the hydrophilic face of the peptide and are composed of all hydrophilic residues, i.e., Glu and Lys. The mathematical formula for defining the hydrophobic face of the AX9 series of peptides can be used to define such a face in any a-helical peptide.

[0061] Regarding (ii) still, and more specifically regarding designing a hydrophilic face, peptide AX7 (FIG. 3) defines what constitutes a hydrophilic helical face. The primary amino acid sequence for a hydrophilic face is based on a 2-1-3-1; 2-1-3-1 repeat. For example, starting with residue 1: 1 + (2) = 3, 3 + (1) = 4, 4 + (3) = 7, 7 + (1) = 8; 8 + (2) = 10, 10 + (1) = 11, H + (3) = 14, 14 + (1) = 15; 15 + (2) = 17 and 17 + (1) = 18; thus, hydrophilic residues, Lys and Glu, are placed at position numbers 1, 3, 4, 7 (guest residue), 8, 10, 11, 14, 15, 17 and 18 in the primary sequence. This arrangement also defines a face which will present those eleven residues on the hydrophilic face of the a-helix. This is depicted on the helical net by drawing two solid lines enclosing those eleven residues. It is further noted that residues El, E8, E15 define a diagonal, K4, Kll, K18 define a second diagonal, for a total of four diagonals. Thus, any diagonal consisting of residues displaced by seven residues will define the position in the primary sequence of the next residue in that diagonal, and any such four adjacent diagonals will define a hydrophilic face on an a-helix. In reference to peptide AX7, all the residues to the left of the left-hand line and to the right of the right-hand line will then constitute the hydrophobic face and are composed of all hydrophobic residues, i.e., Ala. Furthermore, other positioning variations may also prove effective. For example, positive charges may be placed anywhere within AX7, within the constraints of the B 1 + 8 = B2 formula, and tend to increase affinity for HA. Without wishing to limit the present invention to any particular theory or mechanism, it is believed that positive charges best increase affinity for HA when clustered near residue B2. Multiple cationic residues in AX7 can enhance binding. However, oversaturating AX7 with cationic residues can lower the specificity of binding events. Acidic residues like Asp and Glu should generally beReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 excluded from AX7 to maximize affinity for HA, because they can disrupt binding. In general, a balance between positive charge density and amphipathic distribution across the helical face is ideal in order to best increase affinity for HA. The mathematical formula for defining the hydrophilic face of the AX7 series of peptides can be used to define such a face in any a-helical peptide.

[0062] Regarding the design of the AX9 and AX7 peptides, each series of peptides has a “guest residue” at position X9 in the AX9 series and at position X7 in the AX7 series of peptide analogues. The “X” represents each one of the 20 common amino acids, for a total of 20 peptides each for the two sets of peptides analogues.

[0063] One series of analogues (AX9) demonstrated a hydrophobic face, containing three 7-residue diagonals in a helical net, which constitutes a basic helical face of an a-helical peptide. A second series of analogues (AX7) demonstrated a hydrophilic face, that is complimentary to the hydrophobic face of the AX9 series of analogues (i.e., both hydrophobic and hydrophilic faces when combined would reproduce the entire surface of an a-helix). An a-helix contains seven distinct faces presented by a helical surface. The basic helical face (described by the AX9 series of analogues) may be used to analyse HA binding peptides that vary in number and composition of HA binding domains and peptide <pH>, including, for example, 17x-3, peptide #4 and BHP4. Multifaceted analysis revealed that the strong HA binders (including high to moderate specificity) presented helical faces that were optimized designs relative to the positive control peptide mPEP35. For example, and more specifically, 17x-3 presented five HA binding domains in five of the helical faces; whereas, mPEP35 presented four HA binding domains in three helical faces. Optimized versions of the HA binding peptides may be dependent on the distribution of the HA binding domains, resulting in high binding and specificity. Peptides with up to 7 binding domains distributed per 7 faces may thus be designed, but this requires extending peptide length considerably.

[0064] Designing synthetic peptides requires a multifaceted approach in order to incorporate parameters into the peptides that will result in optimal designs. Alpha helical peptides have seven distinct faces as provided by the example minimalistic peptide AX9 analogues, i.e., each face being composed of three 7-residue diagonals. This is evidenced by drastic chromatographic retention time differences if the X9 residue is changed throughout the entire range of amino acid amphipathicity. This is contrasted by the hydrophilic AX7 face, which does not exhibit chromatographic separation as well as the hydrophobic face of the AX9 series of peptides to a C8 hydrophobic column interface. This may be expanded to the family of helical hyaluronic acidReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 binding peptides discussed herein, and evaluated against their binding affinities. When it comes to peptides of very low amphipathicity, one must investigate the very nature of all of the helical faces in order to gain a better understanding of the potential characteristics of the peptide in its entirety, which cannot be assessed by a mere averaging effect that will be obtained from deriving the <pH>. Evaluation of binding criteria and novel hyaluronic acid binding sequences may be performed using computer-assisted methods, based on the differences as examined by the multifaceted analysis of the helical faces of these peptides. The focus of this analysis may be on (1) the arrangements of the B1(X7)B2 binding domains and (2) the hydrophobic to hydrophilic ratio of amino acids in order to assess the most proficient reported biofunctionalities, including hyaluronic acid binding and mitochondrial delivery.

[0065] In some embodiments, the computer-assisted method may further comprise validating a peptide sequence generated by the computer-assisted method by predicting a 3-dimensional structure of the generated peptide sequence. In some embodiments, validation of the peptide sequence may comprise the use of an artificial intelligence (Al) model configured to accept a generated peptide sequence as input and generate a 3 -dimensional structure as output. The Al model may be trained by prior data mapping known peptide sequences to known 3 -dimensional structures. In some embodiments, the computer-assisted method may further comprise simulating molecular docking between a peptide sequence generated by the computer-assisted method and HA. In some embodiments, the computer-assisted method may further comprise determining one or more binding affinities, one or more interactions between the generated peptide sequence and hyaluronic acid, or a combination thereof. The computer-assisted method of the present invention may be executed on any computing system comprising a processor capable of executing computer-readable instructions and a memory component operatively coupled to the processor, configured to contain computer-readable instructions for executing the computer-assisted method. In some embodiments, all steps of the computer-assisted method described above may be stored in the memory component of the computing system as computer-readable instructions. In some embodiments, the memory component may additionally store the Al model.

[0066] The computer system can include a desktop computer, a workstation computer, a laptop computer, a netbook computer, a tablet, a handheld computer (including a smartphone), a server, a supercomputer, a wearable computer (including a SmartWatch™), or the like and can include digital electronic circuitry, firmware, hardware, memory, a computer storage medium, a computer program, a processor (including a programmed processor), an imaging apparatus, wired / wirelessReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 communication components, or the like. The computing system may include a desktop computer with a screen, a tower, and components to connect the two. The tower can store digital images, numerical data, text data, or any other kind of data in binary form, hexadecimal form, octal form, or any other data format in the memory component. The data / images can also be stored in a server communicatively coupled to the computer system. The images can also be divided into a matrix of pixels, known as a bitmap that indicates a color for each pixel along the horizontal axis and the vertical axis. The pixels can include a digital value of one or more bits, defined by the bit depth. Each pixel may comprise three values, each value corresponding to a major color component (red, green, and blue). A size of each pixel in data can range from a 8 bits to 24 bits. The network or a direct connection interconnects the imaging apparatus and the computer system.

[0067] The term "processor" encompasses all kinds of apparatus, devices, and machines for processing data, including by way of example a programmable microprocessor, a microcontroller comprising a microprocessor and a memory component, an embedded processor, a digital signal processor, a media processor, a computer, a system on a chip, or multiple ones, or combinations, of the foregoing. The apparatus can include special-purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit). Logic circuitry may comprise multiplexers, registers, arithmetic logic units (ALUs), computer memory, look-up tables, flip-flops (FF), wires, input blocks, output blocks, read-only memory, randomly accessible memory, electronically-erasable programmable read-only memory, flash memory, discrete gate or transistor logic, discrete hardware components, or any combination thereof. The apparatus also can include, in addition to hardware, code that creates an execution environment for the computer program in question, e.g., code that constitutes processor firmware, a protocol stack, a database management system, an operating system, a cross-platform runtime environment, a virtual machine, or a combination of one or more of them. The apparatus and execution environment can realize various different computing model infrastructures, such as web services, distributed computing and grid computing infrastructures. The processor may include one or more processors of any type, such as central processing units (CPUs), graphics processing units (GPUs), special-purpose signal or image processors, field-programmable gate arrays (FPGAs), tensor processing units (TPUs), and so forth.

[0068] A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpretedReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 languages, declarative or procedural languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, object, or other unit suitable for use in a computing environment. A computer program may, but need not, correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, subprograms, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network.

[0069] Embodiments of the subject matter and the operations described herein can be implemented in digital electronic circuitry, or in computer software, firmware, or hardware, including the structures disclosed in this specification and their structural equivalents, or in combinations of one or more of them. Embodiments of the subject matter described in this specification can be implemented as one or more computer programs, i.e., one or more modules of computer program instructions, encoded on computer storage medium for execution by, or to control the operation of, a data processing apparatus.

[0070] A computer storage medium can be, or can be included in, a computer-readable storage device, a computer-readable storage substrate, a random or serial access memory array or device, or a combination of one or more of them. Moreover, while a computer storage medium is not a propagated signal, a computer storage medium can be a source or destination of computer program instructions encoded in an artificially generated propagated signal. The computer storage medium can also be, or can be included in, one or more separate physical components or media (e.g., multiple CDs, drives, or other storage devices). The operations described in this specification can be implemented as operations performed by a data processing apparatus on data stored on one or more computer-readable storage devices or received from other sources.

[0071] Program code embodied on a computer readable medium may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, R.F, Bluetooth, storage media, computer buses, etc., or any suitable combination of the foregoing. Computer program code for carrying out operations for aspects of the present disclosure may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C#, Ruby, or the like, conventional proceduralReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 programming languages, such as Pascal, FORTRAN, BASIC, or similar programming languages, programming languages that have both object-oriented and procedural aspects, such as the "C" programming language, C++, Python, or the like, conventional functional programming languages such as Scheme, Common Lisp, Elixir, or the like, conventional scripting programming languages such as PHP, Perl, Javascript, or the like, or conventional logic programming languages such as PROLOG, ASAP, Datalog, or the like.

[0072] The program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).

[0073] The processes and logic flows described in this specification can be performed by one or more programmable processors executing one or more computer programs to perform actions by operating on input data and generating output. The processes and logic flows can also be performed by, and apparatus can also be implemented as, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit).

[0074] Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor will receive instructions and data from a read-only memory or a random access memory or both. The essential elements of a computer are a processor for performing actions in accordance with instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto-optical disks, or optical disks.

[0075] However, a computer need not have such devices. Moreover, a computer can be embedded in another device, e.g., a mobile telephone, a personal digital assistant (PDA), a mobile audio or video player, a game console, a Global Positioning System (GPS) receiver, or a portable storage device (e.g., a universal serial bus (USB) flash drive), to name just a few. Devices suitable for storing computer program instructions and data include all forms ofReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 non-volatile memory, media and memory devices, including by way of example semiconductor memory devices, e.g., EPROM, EEPROM, and flash memory devices; magnetic disks, e.g., internal hard disks or removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.

[0076] Computers typically include known components, such as a processor, an operating system, system memory, memory storage devices, input-output controllers, input-output devices, and display devices. It will also be understood by those of ordinary skill in the relevant art that there are many possible configurations and components of a computer and may also include cache memory, a data backup unit, and many other devices. To provide for interaction with a user, embodiments of the subject matter described in this specification can be implemented on a computer having a display device, e.g., an LCD (liquid crystal display), LED (light emitting diode) display, or OLED (organic light emitting diode) display, for displaying information to the user.

[0077] Examples of input devices include a keyboard, cursor control devices (e.g., a mouse or a trackball), a microphone, a scanner, and so forth, wherein the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback provided to the user can be in any form of sensory feedback, e.g., visual feedback, auditory feedback, or tactile feedback; and input from the user can be received in any form, including acoustic, speech, or tactile input. Examples of output devices include a display device (e.g., a monitor or projector), speakers, a printer, a network card, and so forth. Display devices may include display devices that provide visual information, this information typically may be logically and / or physically organized as an array of pixels. In addition, a computer can interact with a user by sending documents to and receiving documents from a device that is used by the user; for example, by sending web pages to a web browser on a user's client device in response to requests received from the web browser.

[0078] An interface controller may also be included that may comprise any of a variety of known or future software programs for providing input and output interfaces. For example, interfaces may include what are generally referred to as “Graphical User Interfaces” (often referred to as GUI’s) that provide one or more graphical representations to a user. Interfaces are typically enabled to accept user inputs using means of selection or input known to those of ordinary skillReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 in the related art. In some implementations, the interface may be a touch screen that can be used to display information and receive input from a user. In the same or alternative embodiments, applications on a computer may employ an interface that includes what are referred to as “command line interfaces” (often referred to as CLI’s). CLI’s typically provide a text based interaction between an application and a user. Typically, command line interfaces present output and receive input as lines of text through display devices. For example, some implementations may include what are referred to as a “shell” such as Unix Shells known to those of ordinary skill in the related art, or Microsoft® Windows Powershell that employs object-oriented type programming architectures such as the Microsoft® .NET framework.

[0079] Those of ordinary skill in the related art will appreciate that interfaces may include one or more GUI’s, CLI’s or a combination thereof. A processor may include a commercially available processor such as a Celeron, Core, or Pentium processor made by Intel Corporation®, a SPARC processor made by Sun Microsystems®, an Athlon, Sempron, Phenom, or Opteron processor made by AMD Corporation®, or it may be one of other processors that are or will become available. Some embodiments of a processor may include what is referred to as multi-core processor and / or be enabled to employ parallel processing technology in a single or multi-core configuration. For example, a multi-core architecture typically comprises two or more processor “execution cores”. In the present example, each execution core may perform as an independent processor that enables parallel execution of multiple threads. In addition, those of ordinary skill in the related field will appreciate that a processor may be configured in what is generally referred to as 32 or 64 bit architectures, or other architectural configurations now known or that may be developed in the future.

[0080] A processor typically executes an operating system, which may be, for example, a Windows type operating system from the Microsoft Corporation®; the Mac OS X operating system from Apple Computer Corp.®; a Unix® or Linux®-type operating system available from many vendors or what is referred to as an open source; another or a future operating system; or some combination thereof. An operating system interfaces with firmware and hardware in a well-known manner, and facilitates the processor in coordinating and executing the functions of various computer programs that may be written in a variety of programming languages. An operating system, typically in cooperation with a processor, coordinates and executes functions of the other components of a computer. An operating system also provides scheduling, input-output control, file and data management, memory management, and communicationReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 control and related services, all in accordance with known techniques.

[0081] Connecting components may be properly termed as computer-readable media. For example, if code or data is transmitted from a website, server, or other remote source using a coaxial cable, fiber optic cable, twisted pair, digital subscriber line (DSL), or wireless technology such as infrared, radio, or microwave signals, then the coaxial cable, fiber optic cable, twisted pair, DSL, or wireless technology are included in the definition of medium. Combinations of media are also included within the scope of computer-readable media.

[0082] The present invention may comprise or implement an Al model comprising a neural network for machine learning tasks. The neural network may be stored, trained, and / or executed entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. The neural network may be stored in the form of program code, as described above. The neural network, in some embodiments, may be a perceptron neural network, a feed forward neural network, a multilayer perceptron neural network, a convolutional neural network, a radial basis functional neural network, a recurrent neural network, a long short-term memory neural network, a sequence-to-sequence neural network model, a modular neural network, or the like.

[0083] EXAMPLE

[0084] The following is a non-limiting example of the present invention. It is to be understood that said example is not intended to limit the present invention in any way. Equivalents or substitutes are within the scope of the present invention.

[0085] Computer-Aided Generation, Validation, Modeling, Docking, and Patent Screening of BX7B Domain Peptides with High Affinity for Hyaluronic Acid: This workflow is designed for the automated generation and subsequent validation, structural modeling, molecular docking, and patent screening of peptide sequences containing specified BX7B domains. It ensures the creation of peptides with high binding affinity for hyaluronic acid and verifies that they do not infringe on the claims of existing patents.

[0086] Application 1. Peptide Sequence Generation: Input Parameters: Number of sequences (num sequences), sequence length (sequence length), number of BX7B domains (num domains). Procedure: The script generates peptide sequences by embedding the specified number of BX7B domains. Each domain consists of a 'K' residue, followed by seven randomlyReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 chosen residues from the set {A, G, I, L, P, V}, and ends with another 'K' residue. Additional residues are appended to meet the total sequence length. Additional Constraints: Specific residue positions (e.g., residues at positions 8, 11, 12, 15, 18, 19, 22, 25, and 26) must belong to the set {L, M, Q, I, F, A, Y, T}. Residue 2 and residue 29 must be one of {N, S, V, YJ.No consecutive non-polar residues except at predefined positions (10, 11, 17, 18, 24, 25). This automated method for generating BX7B peptide sequences includes randomly generating peptide sequences, ensuring the presence of BX7B domains, and validating sequences against specific residue constraints and non-polar checks.

[0087] Application 2. 3DStructural Modeling Using AlphaFold: Input: Validated peptide sequences. Procedure: Each sequence is submitted to AlphaFold, which predicts the 3D structure and saves it as a PDB file. This step can be automated using available AlphaFold APIs or ColabFold, a simplified interface for AlphaFold.

[0088] Application 3. Docking Using HADDOCK and DockTHOR: Input: PDB files of modeled peptide sequences and hyaluronic acid. Procedure: HADDOCK: Perform molecular docking simulations between each peptide model and hyaluronic acid using HADDOCK, generating output files that detail binding affinities and interaction sites. DockTHOR: Similarly, use DockTHOR to dock the peptides and assess their binding affinities and interactions.

[0089] Application 4. Patent Screening: Input: The best-binding peptide sequences. Procedure: TheLensAPI: Submit each sequence to The Lens API to check for potential patent violations. EMBL-EBIPatent Protein Database: Query the database to validate that the sequences do not violate any existing patents.

[0090] EMBODIMENTS

[0091] The following are non-limiting embodiments of the present invention. It is to be understood that said embodiments are not intended to limit the present invention in any way. Equivalents or substitutes are within the scope of the present invention.

[0092] Embodiment 1 : A skin-enhancing compound comprising: a RHAMM-replicating peptide; a delivery component; and a cleavage site linking the RHAMM-replicating peptide and the delivery component; wherein protein-mediated cleavage of the cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing theReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025RHAMM-replicating peptide to associate with hyaluronic acid.

[0093] Embodiment 2: A skin-enhancing cosmetic composition comprising: hyaluronic acid; and one or more skin-enhancing compounds, each comprising: a RHAMM-replicating peptide; a delivery component; and a cleavage site linking the RHAMM-replicating peptide and the delivery component; wherein protein-mediated cleavage of the cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid; wherein the RHAMM-replicating peptide polymerizes with the hyaluronic acid upon cleavage of the delivery component to form a macromolecular gel.

[0094] Embodiment 3: A skin-enhancing compound comprising: a RHAMM-replicating peptide; a delivery component; and a photo-cleavable cleavage site linking the RHAMM-replicating peptide and the delivery component, wherein ultraviolet-mediated cleavage of the photo-cleavable cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid.

[0095] Embodiment 4: A skin-enhancing cosmetic composition comprising: hyaluronic acid; and one or more skin-enhancing compounds, each comprising: a RHAMM-replicating peptide; a delivery component; and a photo-cleavable cleavage site linking the RHAMM-replicating peptide and the delivery component; wherein ultraviolet-mediated cleavage of the photo-cleavable cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid; wherein the RHAMM-replicating peptide polymerizes with the hyaluronic acid to form a macromolecular gel appropriate for topical administration to a subject in need thereof.

[0096] Embodiment 5: The compound of embodiment 1, 3, or 5, wherein the delivery component comprises PEG 200, PEG 300, PEG 400, PEG 600, PEG 900, PEG 1000, PEG 1450, PEG 1540, PEG 2000, PEG 3000, PEG3350, PEG 4000, PEG 4600, or PEG 8000. Embodiment 6: The composition of embodiment 2 or 4, wherein the delivery component comprises PEG 200, PEG 300, PEG 400, PEG 600, PEG 900, PEG 1000, PEG 1450, PEG 1540, PEG 2000, PEG 3000, PEG3350, PEG 4000, PEG 4600, or PEG 8000. Embodiment 7: The compound of embodiment 5, wherein the PEG3350 has a molecular weight of between about 3015 and 3685. Embodiment 8: The composition of embodiment 6, wherein the PEG3350 has a molecular weight of between about 3015 and 3685.

[0097] Embodiment 9: The compound of embodiment 1, wherein the cleavage site comprises a matrix metalloproteinase cleavage site. Embodiment 10: The composition of embodiment 2,Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 wherein the cleavage site comprises a matrix metalloproteinase cleavage site. Embodiment 11 : The compound of embodiment 3, wherein the photo-cleavable cleavage site comprises an o-nitrobenzyl linker, o-Nitrobenzyl linker, an o-nitroveratryl linker, a phenacyl linker, a benzoin linker, or a pivaloyl linker. Embodiment 12: The composition of embodiment 4, wherein the photo-cleavable cleavage site comprises an o-nitrobenzyl linker, o-Nitrobenzyl linker, an o-nitroveratryl linker, a phenacyl linker, a benzoin linker, or a pivaloyl linker.

[0098] Embodiment 13: The compound of any one of embodiments 1, 3, 5, 7, 9, or 11, wherein the RHAMM-replicating peptide comprises: 17x-3, BHP4, or Peptide 4. Embodiment 14: The composition of any one of embodiments 2, 4, 6, 8, 10, or 12, wherein the RHAMM-replicating peptide in the composition is selected from a group consisting of one or more of the following: 17x-3, BHP4, and Peptide 4.

[0099] Embodiment 15: The compound of any one of embodiments 1, 3, 5, 7, 9, 11, or 13, wherein the delivery component is a dermal delivery component or a transdermal delivery component. Embodiment 16: The composition of any one of embodiments 2, 4, 6, 8, 10, 12, or 14, wherein the delivery component is a dermal delivery component or a transdermal delivery component.

[0100] Embodiment 17: The compound of any one of embodiments 1, 3, 5, 7, 9, 11, or 15, wherein the RHAMM-replicating peptide is a sequence according to SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11.

[0101] Embodiment 18: A computer-assisted method for automatically generating peptide sequences containing BX7B domains, each peptide sequence configured to bind to hyaluronic acid. Embodiment 19: A computer-assisted method of embodiment 18 for automatically generating peptide sequences containing BX7B domains, wherein the B(X7)B domains are positionally located as they are described in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, where the hydrophobicity ratio is altered.

[0102] Embodiment 20: The computer-assisted method of embodiment 18 comprising randomly generating one or more peptide sequences, each peptide sequence having a length of at least fourteen positions, each position comprising a residue, wherein each peptide sequence conforms to at least one of the following parameters: a) wherein each peptide sequence of the one or more peptide sequences comprises a first K residue in a first position and a second K residue in a ninth position; b) wherein each peptide sequence of the one or more peptide sequences comprises an LReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 residue, an M residue, a Q residue, an I residue, an F residue, an A residue, a Y residue, or a T residue in an eighth position, an eleventh position, a twelfth position, a fifteenth position, an eighteenth position, a nineteenth position, a twenty-second position, a twenty-fifth position, and a twenty-sixth position; or c) wherein each peptide sequence of the one or more peptide sequences comprises an N residue, an S residue, a V residue, or a Y residue in a second position and a twenty-ninth position.

[0103] Embodiment 21 : The computer-assisted method of embodiment 18 comprising randomly generating one or more peptide sequences, each peptide sequence having a length of at least fifteen positions, each position comprising a residue, wherein each peptide sequence conforms to at least one of the following parameters: a) wherein each peptide sequence of the one or more peptide sequences comprises a first K residue in a first position and a second K residue in a ninth position; b) wherein each peptide sequence of the one or more peptide sequences comprises an L residue, an M residue, a Q residue, an I residue, an F residue, an A residue, a Y residue, or a T residue in an eighth position, an eleventh position, a twelfth position, a fifteenth position, an eighteenth position, a nineteenth position, a twenty-second position, a twenty-fifth position, and a twenty-sixth position; or c) wherein each peptide sequence of the one or more peptide sequences comprises an N residue, an S residue, a V residue, or a Y residue in a second position and a twenty-ninth position.

[0104] Embodiment 22: The computer-assisted method of embodiment 18, embodiment 19, embodiment 20, or embodiment 21, further comprising introducing additional B1(X7)B2 domains, said B1(X7)B2 domains having positive charges, thereby increasing interactions between hyaluronic acid and a peptide having the automatically generated peptide sequence.

[0105] Embodiment 23: The computer-assisted method of embodiment 20, wherein each peptide sequence of the one or more peptide sequences comprises consecutive non-polar residues only at a tenth position and the eleventh position, a seventeenth position and the eighteenth position, and a twenty-fourth position and the twenty-fifth position. Embodiment 24: The computer-assisted method of embodiment 20 further comprising validating a peptide sequence generated by the computer-assisted method by predicting a 3 -dimensional structure of the peptide sequence.

[0106] Embodiment 25: The computer-assisted method of embodiment 20 further comprising simulating molecular docking between a peptide sequence generated by the computer-assisted method and hyaluronic acid. Embodiment 26: The computer-assisted method of embodiment 25 further comprising determining one or more binding affinities, one or more molecular interactions between the peptide sequence and hyaluronic acid, or a combination thereof; whereinReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 molecular interactions comprise at least one of electrostatic interactions, hydrogen bonding, hydrophobic interactions, TI- TI interactions, cation-7t interactions, Van der Waals interactions, or water-mediated interactions. Embodiment 27: The computer-assisted method of embodiment 20 further comprising determining if a peptide sequence generated by the computer-assisted method is described in a patent application or patent, wherein determining comprises querying a computer-mediated patent database with the peptide sequence and validating the peptide sequence if no matches are found in the computer-mediated patent database.

[0107] Embodiment 28: A composition comprising the skin-enhancing compound of any one of embodiments 1, 3, 5, 7, 9, 11, 13, 15, or 17 and hyaluronic acid. Embodiment 29: A method of enhancing at least one of the hydration, texture, healing, or elasticity of skin comprising administering a composition according to any one of embodiments 2, 4, 6, 8, 10, 12, 14, 16, or 28.

[0108] As used herein, the term “about” refers to plus or minus 10% of the referenced number.

[0109] Although there has been shown and described the preferred embodiment of the present invention, it will be readily apparent to those skilled in the art that modifications may be made thereto which do not exceed the scope of the appended claims. Therefore, the scope of the invention is only to be limited by the following claims. In some embodiments, the figures presented in this patent application are drawn to scale, including the angles, ratios of dimensions, etc. In some embodiments, the figures are representative only and the claims are not limited by the dimensions of the figures. In some embodiments, descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as “consisting essentially of’ or “consisting of’, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase “consisting essentially of’ or “consisting of’ is met.

Claims

Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025WHAT IS CLAIMED IS:

1. A skin-enhancing compound comprising: a RHAMM-replicating peptide; a delivery component; and a cleavage site linking the RHAMM-replicating peptide and the delivery component; wherein protein-mediated cleavage of the cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid.

2. A skin-enhancing cosmetic composition comprising: hyaluronic acid; and one or more skin-enhancing compounds, each comprising: a RHAMM-replicating peptide; a delivery component; and a cleavage site linking the RHAMM-replicating peptide and the delivery component; wherein protein-mediated cleavage of the cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid; wherein the RHAMM-replicating peptide polymerizes with the hyaluronic acid upon cleavage of the delivery component to form a macromolecular gel.

3. A skin-enhancing compound comprising: a RHAMM-replicating peptide; a delivery component; and a photo-cleavable cleavage site linking the RHAMM-replicating peptide and the delivery component wherein ultraviolet-mediated cleavage of the photo-cleavable cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid.

4. A skin-enhancing cosmetic composition comprising: hyaluronic acid; and one or more skin-enhancing compounds, each comprising: a RHAMM-replicating peptide; a delivery component; andReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 a photo-cleavable cleavage site linking the RHAMM-replicating peptide and the delivery component; wherein ultraviolet-mediated cleavage of the photo-cleavable cleavage site separates the RHAMM-replicating peptide from the delivery component, thereby allowing the RHAMM-replicating peptide to associate with hyaluronic acid; wherein the RHAMM-replicating peptide polymerizes with the hyaluronic acid upon cleavage of the delivery component to form a macromolecular gel.

5. The compound of claim 1, 3, or 4, wherein the delivery component comprises PEG 200, PEG 300, PEG 400, PEG 600, PEG 900, PEG 1000, PEG 1450, PEG 1540, PEG 2000, PEG 3000, PEG3350, PEG 4000, PEG 4600, or PEG 8000.

6. The composition of claim 2 or 4, wherein the delivery component comprises PEG 200, PEG 300, PEG 400, PEG 600, PEG 900, PEG 1000, PEG 1450, PEG 1540, PEG 2000, PEG 3000, PEG3350, PEG 4000, PEG 4600, or PEG 8000.

7. The compound of claim 5, wherein the PEG3350 has a molecular weight of between about 3015 and 3685.

8. The composition of claim 6, wherein the PEG3350 has a molecular weight of between about 3015 and 3685.

9. The compound of claim 1, wherein the cleavage site comprises a matrix metalloproteinase cleavage site.

10. The composition of claim 2, wherein the cleavage site comprises a matrix metalloproteinase cleavage site.

11. The compound of claim 3, wherein the photo-cleavable cleavage site comprises an o-nitrobenzyl linker, o-Nitrobenzyl linker, an o-nitroveratryl linker, a phenacyl linker, a benzoin linker, or a pivaloyl linker.

12. The composition of claim 4, wherein the photo-cleavable cleavage site comprises an o-nitrobenzyl linker, o-Nitrobenzyl linker, an o-nitroveratryl linker, a phenacyl linker, a benzoin linker, or a pivaloyl linker.

13. The compound of any one of claims 1, 3, 5, 7, 9, or 11, wherein the RHAMM-replicating peptide comprises: 17x-3, BHP4, or Peptide 4.

14. The composition of any one of claims 2, 4, 6, 8, 10, or 12, wherein the RHAMM-replicating peptide in the composition is selected from a group consisting of one or more of the following: 17x-3, BHP4, and Peptide 4.

15. The compound of any one of claims 1, 3, 5, 7, 9, 11, or 13, wherein the deliveryReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 component is a dermal delivery component or a transdermal delivery component.

16. The composition of any one of claims 2, 4, 6, 8, 10, 12, or 14, wherein the delivery component is a dermal delivery component or a transdermal delivery component.

17. The compound of any one of claims 1, 3, 5, 7, 9, 11, or 15, wherein the RHAMM-replicating peptide is a sequence according to SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11.

18. A computer-assisted method for automatically generating peptide sequences containing BX7B domains, each peptide sequence configured to bind to hyaluronic acid.

19. A computer-assisted method of claim 18 for automatically generating peptide sequences containing BX7B domains, wherein the B(X7)B domains are positionally located as they are described in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11, where the hydrophobicity ratio is altered.

20. The computer-assisted method of claim 18 comprising randomly generating one or more peptide sequences, each peptide sequence having a length of at least fourteen positions, each position comprising a residue, wherein each peptide sequence conforms to at least one of the following parameters: a) wherein each peptide sequence of the one or more peptide sequences comprises a first K residue in a first position and a second K residue in a ninth position; b) wherein each peptide sequence of the one or more peptide sequences comprises an L residue, an M residue, a Q residue, an I residue, an F residue, an A residue, a Y residue, or a T residue in an eighth position, an eleventh position, a twelfth position, a fifteenth position, an eighteenth position, a nineteenth position, a twenty-second position, a twenty-fifth position, and a twenty-sixth position; or c) wherein each peptide sequence of the one or more peptide sequences comprises an N residue, an S residue, a V residue, or a Y residue in a second position and a twenty-ninth position.

21. The computer-assisted method of claim 18 comprising randomly generating one or more peptide sequences, each peptide sequence having a length of at least fifteenReference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025 positions, each position comprising a residue, wherein each peptide sequence conforms to at least one of the following parameters: a) wherein each peptide sequence of the one or more peptide sequences comprises a first K residue in a first position and a second K residue in a ninth position; b) wherein each peptide sequence of the one or more peptide sequences comprises an L residue, an M residue, a Q residue, an I residue, an F residue, an A residue, a Y residue, or a T residue in an eighth position, an eleventh position, a twelfth position, a fifteenth position, an eighteenth position, a nineteenth position, a twenty-second position, a twenty-fifth position, and a twenty-sixth position; or c) wherein each peptide sequence of the one or more peptide sequences comprises an N residue, an S residue, a V residue, or a Y residue in a second position and a twenty-ninth position.

22. The computer-assisted method of claim 18, claim 19, claim 20, or claim 21, further comprising introducing additional B1(X7)B2 domains, said B1(X7)B2 domains having positive charges, thereby increasing interactions between hyaluronic acid and a peptide having the automatically generated peptide sequence.

23. The computer-assisted method of claim 20, wherein each peptide sequence of the one or more peptide sequences comprises consecutive non-polar residues only at a tenth position and the eleventh position, a seventeenth position and the eighteenth position, and a twenty-fourth position and the twenty -fifth position.

24. The computer-assisted method of claim 20 further comprising validating a peptide sequence generated by the computer-assisted method by predicting a 3-dimensional structure of the peptide sequence.

25. The computer-assisted method of claim 20 further comprising simulating molecular docking between a peptide sequence generated by the computer-assisted method and hyaluronic acid.

26. The computer-assisted method of claim 25 further comprising determining one or more binding affinities, one or more molecular interactions between the peptide sequence and hyaluronic acid, or a combination thereof; wherein molecular interactions comprise at least one of electrostatic interactions, hydrogen bonding, hydrophobic interactions, TI- TI interactions, cation-7t interactions,Reference No.: ARIZ 24.31 PCT Inventor’s last name: Koss et al.Document Date: 10 / 6 / 2025Van der Waals interactions, or water-mediated interactions.

27. The computer-assisted method of claim 20 further comprising determining if a peptide sequence generated by the computer-assisted method is described in a patent application or patent, wherein determining comprises querying a computer-mediated patent database with the peptide sequence and validating the peptide sequence if no matches are found in the computer-mediated patent database.

28. A composition comprising the skin-enhancing compound of any one of claims 1, 3, 5, 7, 9, 11, 13, 15, or 17 and hyaluronic acid.

29. A method of enhancing at least one of the hydration, texture, healing, or elasticity of skin comprising administering a composition according to any one of claims 2, 4, 6, 8, 10, 12, 14, 16, or 28.

30. The composition of any one of claims 2, 4, 6, 8, 10, 12, 14, 16, wherein the RHAMM-replicating peptide is a sequence according to SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, or SEQ ID NO: 11.

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