Peptide inhibitors of sting

Abstract

Peptide inhibitors of STING, pharmaceutical formulations containing these inhibitors, and methods of using them to treat STING associated diseases are presented.

Description

Attorney Docket No.: ARCI-002WO PEPTIDE INHIBITORS OF STING CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of United States Provisional Application No.63 / 696,307, filed September 18, 2024, the disclosure of which is incorporated herein by reference in its entirety. INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING XML

[0002] A Sequence Listing is provided herewith as a Sequence Listing XML, “ARCI- 002WO_SEQ_LIST” created on September 17, 2025, and having a size of 76,671 bytes. The contents of the Sequence Listing XML are incorporated by reference herein in their entirety. BACKGROUND OF THE INVENTION

[0003] Stimulator of Interferon Genes (STING), is a protein whose activation leads to the production of type-I interferons and other interferon-induced genes. This production occurs to mount an innate immune response to a detected threat in the body, such as the presence of cytosolic double-stranded DNA (dsDNA) or DNA / RNA hybrids. Activation of STING in responder cells, including fibroblasts, macrophages, and endothelial cells, elicit downstream anti-cancer and anti-viral immune responses, but can also exacerbate systemic inflammation and autoimmunity.

[0004] The discovery of new inhibitors of STING would be an advancement in the art. This, and other advancements, are described herein. SUMMARY OF THE INVENTION

[0005] The present disclosure relates generally to compounds for inhibiting STING, pharmaceutical formulations comprising those compounds, methods of inhibiting STING, and methods of treating STING associated diseases.

[0006] The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative embodiments and features described herein, further aspects, embodiments, objects and features of the disclosure will become fully apparent from the drawings and the detailed description and the claims.Attorney Docket No.: ARCI-002WO BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0008] FIG 1 shows an automated solid-phase peptide synthesis protocol for peptide inhibitors of the invention.

[0009] FIG 2 shows a cyclization strategy for peptide inhibitors of the invention.

[0010] FIG 3 shows the results of a Blue-Native PAGE experiment performed using purified peptide inhibitors of the invention (e.g. PI 2).

[0011] FIG 4 shows the results of a Blue-Native assay demonstrating a dose-dependent reduction in STING oligomerization in both stimulated wild-type STING and unstimulated R284S STING. This indicates that PI 2 inhibited human STING oligomerization. DETAILED DESCRIPTION OF THE INVENTION I. Definitions

[0012] Unless otherwise defined, all terms of art, notations, and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this application pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Many of the techniques and procedures described or referenced herein are well understood and commonly employed using conventional methodology by those skilled in the art.

[0013] The singular form “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes one or more cells, comprising mixtures thereof. “A and / or B” is used herein to include all of the following alternatives: “A”, “B”, “A or B”, and “A and B”.

[0014] The terms “administration” and “administering”, as used herein, refer to the delivery of a bioactive composition or formulation by an administration route comprising, but notAttorney Docket No.: ARCI-002WO limited to, intranasal, transdermal, intravenous, intra-arterial, intramuscular, intranodal, intraperitoneal, subcutaneous, intramuscular, oral, intravaginal, and topical administration, or combinations thereof. The term includes, but is not limited to, administering by a medical professional and self-administering.

[0015] The term “effective amount”, “therapeutically effective amount”, or “pharmaceutically effective amount” of a composition of the disclosure, e.g., nucleic acid constructs, srRNAs, recombinant cells, and / or pharmaceutical compositions, generally refers to an amount sufficient for the composition to accomplish a stated purpose relative to the absence of the composition (e.g., achieve the effect for which it is administered, stimulate an immune response, prevent or treat a disease, or reduce one or more symptoms of a disease, disorder, infection, or health condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). The exact amount of a composition including a “therapeutically effective amount” will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0016] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0017] Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recitedAttorney Docket No.: ARCI-002WO number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. If the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. In some embodiments, the term “about” indicates the designated value ± up to 10%, up to ± 5%, or up to ± 1%.

[0018] The term “pharmaceutically acceptable excipient” as used herein refers to any suitable substance that provides a pharmaceutically acceptable carrier, additive, or diluent for administration of a compound(s) of interest to a subject. As such, “pharmaceutically acceptable excipient” can encompass substances referred to as pharmaceutically acceptable diluents, pharmaceutically acceptable additives, and pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” includes, but is not limited to, saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds (e.g., antibiotics and additional therapeutic agents) can also be incorporated into the compositions.

[0019] As used herein, a “subject” or an “individual” includes animals, such as human (e.g., human individuals) and non-human animals. In some embodiments, a “subject” or “individual” is a patient under the care of a physician. Thus, the subject can be a human patient or an individual who has, is at risk of having, or is suspected of having a health condition of interest (e.g., rabies infection) and / or one or more symptoms of the health condition. The subject can also be an individual who is diagnosed with a risk of the health condition of interest at the time of diagnosis or later. The term “non-human animals” includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, non-human primates, and other mammals, such as e.g., sheep, dogs, cows, chickens, and non-mammals, such as amphibians, reptiles, etc.

[0020] It is understood that aspects and embodiments of the disclosure described herein include "comprising", "consisting", and "consisting essentially of" aspects and embodiments. As used herein, "comprising" is synonymous with "including", "containing", or "characterized by", and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any elements, steps, or ingredients not specified in the claimed composition or method. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic andAttorney Docket No.: ARCI-002WO novel characteristics of the claimed composition or method. Any recitation herein of the term "comprising", particularly in a description of components of a composition or in a description of steps of a method, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or steps.

[0021] All genes, gene names, and gene products disclosed herein are intended to correspond to homologs from any species for which the compositions and methods disclosed herein are applicable. Thus, the terms include, but are not limited to genes and gene products from humans and mice. It is understood that when a gene or gene product from a particular species is disclosed, this disclosure is intended to be exemplary only, and is not to be interpreted as a limitation unless the context in which it appears clearly indicates. Thus, for example, for the genes or gene products disclosed herein, which in some embodiments relate to mammalian nucleic acid and amino acid sequences, are intended to encompass homologous and / or orthologous genes and gene products from other animals including, but not limited to other mammals, fish, amphibians, reptiles, and birds. In some embodiments, the genes, nucleic acid sequences, amino acid sequences, peptides, polypeptides and proteins are human. The term “gene” is also intended to include variants thereof.

[0022] The terms ''peptide," ''polypeptide," and "protein" are used interchangeably herein, and refer to a polymeric form of amino acids of any length, which can include coded (e.g. natural) and / or non-coded (e.g. unnatural) amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. In an exemplary embodiment, one or more of the bonds of the peptide backbone are modified. In an exemplary embodiment, the peptide backbone has one or more amide bonds. In an exemplary embodiment, the peptide backbone has one or more eupeptide bonds. In an exemplary embodiment, the peptide backbone has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 eupeptide bonds. In an exemplary embodiment, the peptide backbone has 13 eupeptide bonds.

[0023] The term “amino acid” generally refers to any monomer unit that comprises a substituted or unsubstituted amino group or an analog thereof, a substituted or unsubstituted carboxy group or an analog thereof, and one or more side chains or analog thereof. Exemplary side chains include, e.g., thiol, seleno, sulfonyl, alkyl, aryl, acyl, keto, azido, hydroxyl, hydrazine, cyano, halo, hydrazide, alkenyl, alkynl, ether, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, ester, thioacid, hydroxylamine, or any combination of these groups. Other representative amino acidsAttorney Docket No.: ARCI-002WO include, but are not limited to, amino acids comprising photoactivatable cross-linkers, metal binding amino acids, spin-labeled amino acids, fluorescent amino acids, metal-containing amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and / or photoisomerizable amino acids, radioactive amino acids, amino acids comprising biotin or a biotin analog, glycosylated amino acids, other carbohydrate modified amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and / or photocleavable amino acids, carbon-linked sugar-containing amino acids, redox- active amino acids, amino thioacid containing amino acids, and amino acids comprising one or more toxic moieties.

[0024] The term “amino acid” includes, but is not limited to, naturally-occurring α-amino acids and their stereoisomers. “Stereoisomers” of amino acids refer to mirror image isomers of the amino acids, such as L-amino acids or D-amino acids. For example, a stereoisomer of a naturally-occurring amino acid refers to the mirror image isomer of the naturally-occurring amino acid (i.e., the D-amino acid).

[0025] Naturally-occurring α-amino acids (also referred to as “natural amino acids”) are those encoded by the genetic code as well as those amino acids that are later modified (e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine). Naturally-occurring α-amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof. Stereoisomers of a naturally-occurring α-amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic acid (D-Asp), D- glutamic acid (D-Glu), D-phenylalanine (D-Phe), D-histidine (D-His), D-isoleucine (D-Ile), D-arginine (D-Arg), D-lysine (D-Lys), D-leucine (D-Leu), D-methionine (D-Met), D- asparagine (D-Asn), D-proline (D-Pro), D-glutamine (D-Gln), D-serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D-tryptophan (D-Trp), D-tyrosine (D-Tyr), and combinations thereof.

[0026] The term “unnatural amino acid” includes those outside of the natural amino acids. Exemplary side chains of an unnatural amino acid include, e.g., thiol (excluding cysteine and methionine), seleno, sulfonyl, alkyl (excluding alanine, valine, leucine, isoleucine), aryl (excluding tyrosine and phenylalanine), acyl, keto, azido, hydroxyl (excluding serine andAttorney Docket No.: ARCI-002WO threonine), hydrazine, cyano, halo, hydrazide, alkenyl, alkynl, ether, borate, boronate, phospho, phosphono, phosphine, heterocyclic (excluding tryptophan and proline), enone, imine, aldehyde, ester, thioacid, hydroxylamine, or any combination of these groups. Other representative unnatural amino acids include, but are not limited to, amino acids comprising photoactivatable cross-linkers, metal binding amino acids, spin-labeled amino acids, fluorescent amino acids, metal-containing amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and / or photoisomerizable amino acids, radioactive amino acids, amino acids comprising biotin or a biotin analog, glycosylated amino acids, other carbohydrate modified amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and / or photocleavable amino acids, carbon- linked sugar-containing amino acids, redox- active amino acids, amino thioacid containing amino acids, and amino acids comprising one or more toxic moieties.

[0027] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Commission on Biochemical Nomenclature. For example, an L-amino acid may be represented herein by its commonly known three letter symbol (e.g., Arg for L-arginine) or by an upper-case one-letter amino acid symbol (e.g., R for L-arginine). A D-amino acid may be represented herein by its commonly known three letter symbol (e.g., D-Arg for D-arginine) or by a lower-case one- letter amino acid symbol (e.g., r for D-arginine).

[0028] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the disclosure are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub- combinations of the various embodiments and elements thereof are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.Attorney Docket No.: ARCI-002WO II. Introduction

[0029] A hallmark of cancer is the presence of double-stranded DNA in the cytosol, resulting from chromosomal instability, damaged mitochondria, extrachromosomal DNA replication or treatment-induced chromatin bridges. The innate immune pattern recognition receptor cGAS, upon recognizing cytosolic dsDNA, is activated to produce the second messenger cGAMP. cGAMP is a potent activator of its ER transmembrane receptor STING (Stimulator of Interferon Genes), which scaffolds the recruitment and activation of kinase TBK1 and transcription factor IRF3, and ultimately stimulating type-I interferon gene expression. III. Peptides

[0030] In one aspect, the invention comprises a peptide of the invention. In an exemplary embodiment, the invention comprises a peptide described herein, or a salt thereof. In an exemplary embodiment, the invention comprises a peptide inhibitor described herein, or a salt thereof. In an exemplary embodiment, the invention consists of a peptide described herein, or a salt thereof. In an exemplary embodiment, the invention consists of a peptide inhibitor described herein, or a salt thereof. In an exemplary embodiment, the invention consists essentially a peptide described herein, or a salt thereof. In an exemplary embodiment, the invention consists essentially of a peptide inhibitor described herein, or a salt thereof. In an exemplary embodiment, the invention comprises a peptide inhibitor of Table 1, or a salt thereof. In an exemplary embodiment, the invention comprises a peptide inhibitor of Table 3, or a salt thereof.

[0031] In an exemplary embodiment, the invention is a peptide, or a salt thereof, comprising a structure of Formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(I) wherein X1is a natural amino acid or an unnatural amino acid; X2is tryptophan or aspartic acid; X3is a natural amino acid or an unnatural amino acid; X4is a natural amino acid or an unnatural amino acid; X5is a natural amino acid or an unnatural amino acid; X6is a natural amino acid or an unnatural amino acid; X7is a natural amino acid or an unnatural amino acid; X8is isoleucine, phenylalanine, or tryptophan; X9is leucine, isoleucine, phenylalanine, tryptophan, or glycine; X10is isoleucine, tryptophan, or threonine; X11is isoleucine, phenylalanine, cysteine, valine, tryptophan, or leucine; X12is a natural amino acid or an unnatural amino acid; X13is a natural amino acid or an unnatural amino acid; wherein X1and X13are optionally covalently attached.Attorney Docket No.: ARCI-002WO

[0032] In an exemplary embodiment, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, valine, leucine, methionine, arginine, histidine, alanine, threonine, serine, lysine, cysteine, glycine, or glutamine. In an exemplary embodiment, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, valine, leucine, methionine, arginine, histidine, alanine, or threonine. In an exemplary embodiment, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X3is arginine, histidine, alanine, or threonine. In an exemplary embodiment, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X3is leucine or methionine. In an exemplary embodiment, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, or valine. In an exemplary embodiment, X1, X2, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X3is asparagine.

[0033] In an exemplary embodiment, X1, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X4is cysteine, alanine, arginine, methionine, leucine, lysine, phenylalanine, serine, valine, tyrosine, isoleucine, tryptophan, or histidine. In an exemplary embodiment, X1, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X4is cysteine, alanine, arginine, methionine, leucine, phenylalanine, serine, valine, tyrosine, isoleucine, tryptophan, or histidine. In an exemplary embodiment, X1, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X4is cysteine, alanine, arginine, methionine, leucine, or histidine. In an exemplary embodiment, X1, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X4is valine, tyrosine, isoleucine, or tryptophan. In an exemplary embodiment, X1, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X4is phenylalanine. In an exemplary embodiment, X1, X2, X3, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X4is serine.

[0034] In an exemplary embodiment, X1, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X5is asparagine, lysine, cysteine, alanine, serine, threonine, histidine, methionine, arginine, glutamine, tryptophan, phenylalanine, isoleucine, tyrosine, valine, leucine, or proline. In an exemplary embodiment, X1, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X5is lysine, cysteine, alanine, serine, threonine, histidine, methionine, arginine, glutamine, tryptophan, phenylalanine, isoleucine, tyrosine, valine, or leucine. In an exemplary embodiment, X1, X2, X3, X4, X6, X7, X8, X9,Attorney Docket No.: ARCI-002WO X10, X11, X12, and X13are as described herein, and X5is lysine, cysteine, alanine, serine, threonine, histidine, methionine, or arginine. In an exemplary embodiment, X1, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X5is tryptophan, phenylalanine, isoleucine, tyrosine, valine, or leucine. In an exemplary embodiment, X1, X2, X3, X4, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X5is glutamine.

[0035] In an exemplary embodiment, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X6is arginine, isoleucine, valine, leucine, histidine, tyrosine, tryptophan, threonine, or cysteine. In an exemplary embodiment, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X6is isoleucine, valine, leucine, histidine, tyrosine, tryptophan, threonine, or cysteine. In an exemplary embodiment, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X6is threonine or cysteine. In an exemplary embodiment, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X6is tyrosine. In an exemplary embodiment, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X6is isoleucine, valine, leucine, histidine, or tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X6is histidine.

[0036] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13are as described herein, and X7is asparagine, histidine, phenylalanine, isoleucine, tryptophan, arginine, tyrosine, leucine, threonine, alanine, methionine, or valine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13are as described herein, and X7is histidine, phenylalanine, isoleucine, tryptophan, tyrosine, leucine, threonine, alanine, methionine, or valine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13are as described herein, and X7is threonine, alanine, or methionine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13are as described herein, and X7is valine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13are as described herein, and X7is histidine, phenylalanine, isoleucine, tryptophan, tyrosine, or leucine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X8, X9, X10, X11, X12, and X13are as described herein, and X7is histidine.

[0037] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13are as described herein, and X8is phenylalanine or tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13are as described herein, and X8is isoleucine.Attorney Docket No.: ARCI-002WO

[0038] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13are as described herein, and X9is leucine, isoleucine, phenylalanine, or tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13are as described herein, and X9is isoleucine, phenylalanine, or tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13are as described herein, and X9is leucine.

[0039] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13are as described herein, and X10is isoleucine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13are as described herein, and X10is tryptophan.

[0040] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13are as described herein, and X11is isoleucine, phenylalanine, or cysteine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13are as described herein, and X11is tryptophan.

[0041] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13are as described herein, and X12is isoleucine, phenylalanine, leucine, histidine, alanine, methionine, cysteine, arginine, serine, threonine, tryptophan, valine, or tyrosine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13are as described herein, and X12is histidine, alanine, methionine, cysteine, arginine, or serine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13are as described herein, and X12is leucine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13are as described herein, and X12is isoleucine, phenylalanine, threonine, tryptophan, valine, or tyrosine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X13are as described herein, and X12is threonine.

[0042] In an exemplary embodiment, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, and X13are as described herein, and X1is tyrosine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12are as described herein, and X13is cysteine. In an exemplary embodiment, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12are as described herein, and X1is tyrosine and X13is cysteine. In an exemplary embodiment, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12are as described herein, and X1is cysteine and X13is tyrosine.Attorney Docket No.: ARCI-002WO

[0043] In an exemplary embodiment, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12are as described herein, and X1has a structure orrepresents a covalent attachment to X2; R4is H or a or C(O)CH2Cl; X13has a structure which is wherein represents a covalentgroup, wherein R2and R3are optionally covalently attached, wherein then X13is13then X is . In an exemplary embodiment, X2, X3, X4, X5, X6, X7, X8, X9,herein, and X1has a structure which isAttorney Docket No.: ARCI-002WO a covalent attachment to X2; R4is H or a a structure which is, wherein represents a covalent attachment to X12; R1is NH2; andgroup; wherein R2and R3are covalently attached. In an exemplary embodiment, each of X1-X2, X2-X3, X3-X4, X4-X5, X5-X6, X6-X7, X7-X8, X8-X9, X9-X10, X10- X11, X11-X12, and X12-X13are covalently attached through an eupeptide bond.

[0044] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X9, X12, and X13are as described herein, and X10is tryptophan and X11is tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X10, X12, and X13are as described herein, and X9is leucine and X11is tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X9, X10, X12, and X13are as described herein, and X8is isoleucine and X11is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X8, X9, X10, X12, and X13are as described herein, and X2is tryptophan and X11is tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X11, X12, and X13are as described herein, and X9is leucine and X10is tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X9, X11, X12, and X13are as described herein, and X8is isoleucine and X10is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X8, X9, X11, X12, and X13are as described herein, and X2is tryptophan and X10is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X8, X10, X11, X12, and X13are as described herein, X2is tryptophan and X9is leucine. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X10, X11, X12, and X13are as described herein, and X8is isoleucine and X9is leucine. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X9, X10, X11, X12, and X13are as described herein, and X2is tryptophan and X8is isoleucine.

[0045] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X8, X12, and X13are as described herein, and X9is leucine, X10is tryptophan, and X11is tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X10, X12, and X13are as described herein, and X8is isoleucine, X9is leucine, and X11is tryptophan. In an exemplary embodiment, X1, X3, X4,Attorney Docket No.: ARCI-002WO X5, X6, X7, X9, X10, X12, and X13are as described herein, and X2is tryptophan, X8is isoleucine, and X11is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X8, X9, X12, and X13are as described herein, and X2is tryptophan, X10is tryptophan, and X11is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X8, X10, X12, and X13are as described herein, and X2is tryptophan, X9is leucine, and X11is tryptophan. In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X11, X12, and X13are as described herein, and X8is isoleucine, X9is leucine, and X10is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X8, X11, X12, and X13are as described herein, and X2is tryptophan, X9is leucine, and X10is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X9, X11, X12, and X13are as described herein, and X2is tryptophan, X8is isoleucine, and X10is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X10, X11, X12, and X13are as described herein, and X2is tryptophan, X8is isoleucine, and X9is leucine.

[0046] In an exemplary embodiment, X1, X2, X3, X4, X5, X6, X7, X12, and X13are as described herein, and X8is isoleucine, X9is leucine, X10is tryptophan, and X11is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X8, X12, and X13are as described herein, and X2is tryptophan, X9is leucine, X10is tryptophan, and X11is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X10, X12, and X13are as described herein, and X2is tryptophan, X8is isoleucine, X9is leucine, and X11is tryptophan. In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X11, X12, and X13are as described herein, and X2is tryptophan, X8is isoleucine, X9is leucine, and X10is tryptophan.

[0047] In an exemplary embodiment, X1, X3, X4, X5, X6, X7, X12, and X13are as described herein, and X2is tryptophan, X8is isoleucine, X9is leucine, X10is tryptophan, and X11is tryptophan. In an exemplary embodiment, X1and X13are as described herein, X2is tryptophan, X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, or valine, X4is phenylalanine or serine, X5is glutamine, X6is isoleucine, valine, leucine, or histidine, X7is histidine, phenylalanine, isoleucine, tryptophan, tyrosine, or leucine, X8is isoleucine, X9is leucine, X10is tryptophan, X11is tryptophan, and X12is threonine or valine. In an exemplary embodiment, X1and X13are as described herein, X2is tryptophan, X3is asparagine, X4is serine, X5is glutamine, X6is histidine, X7is histidine, X8is isoleucine, X9is leucine, X10is tryptophan, X11is tryptophan, and X12is threonine.Attorney Docket No.: ARCI-002WO

[0048] In an exemplary embodiment, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12are as described herein, and X1has a structure orrepresents a covalent attachment to X2; R4is H or a or C(O)CH2Cl; X13has a structure which is wherein represents a covalentgroup, wherein R2and R3are optionally covalently attached, wherein then X13is13then X is are covalently attached (e.g. through a cyclizationembodiment, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12are as described herein, and the X13-X1has a structure which isAttorney Docket No.: ARCI-002WO **wherein R2and R3are optionally covalently attached, wherein when X1is H.comprising a structure of Formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(I)Attorney Docket No.: ARCI-002WO wherein X1has a structure , wherein represents a covalent attachment to X2; R4is R3is H or C(O)CH2Cl; X2is tryptophan or aspartic acid; X3isor valine; X4is lysine, serine, or histidine; X5is asparagine, glutamine, or proline; X6is arginine, histidine, or tryptophan; X7is asparagine, histidine, arginine, or leucine; X8is isoleucine or tryptophan; X9is leucine or glycine; X10is tryptophan or threonine; X11is valine, tryptophan, or leucine; X12is serine, threonine, valine, or tyrosine; X13has a structure , wherein represents a covalent attachment to X12; R1is NH2;group; wherein each of X1-X2, X2-X3, X3-X4, X4-X5, X5-X6, X6-X7, X7-X8, X8-X9, X9-X10, X10-X11, X11-X12, and X12-X13are covalently attached through an eupeptide bond; and R2and R3are optionally covalently attached. IV. Pharmaceutical Formulations

[0050] In another aspect, the invention provides a pharmaceutical formulation comprising: a) the compound, or a pharmaceutically acceptable salt thereof, of any of the preceding claims; and b) one or more pharmaceutically acceptable excipients. In an exemplary embodiment, the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form.

[0051] The pharmaceutical formulations of the invention can take a variety of forms adapted to the chosen route of administration. V. Nucleic Acids, Vectors, Cells

[0052] In an exemplary embodiment, the invention provides nucleic acids that encode a peptide described herein. Vectors comprising such nucleic acids are also described herein. Cells comprising peptides and / or nucleic acids of the invention are also provided.Attorney Docket No.: ARCI-002WO VI. Methods of inhibiting STING

[0053] In another aspect, the invention provides a method of inhibiting STING, comprising: contacting the STING with a compound described herein, or a salt thereof, thereby inhibiting STING. VII. Methods of treating STING associated diseases

[0054] In another aspect, the invention provides a method of treating a STING associated disease in a mammal, comprising: administering to the mammal in need of treatment thereof a therapeutically effective amount of a compound described herein, or a salt thereof, thereby thereby treating the STING associated disease. In an exemplary embodiment, the STING associated disease is an autoimmune disease or a neurodegenerative disease. In an exemplary embodiment, the STING associated disease is an autoimmune disease, which is lupus, multiple sclerosis, or STING-associated vasculopathy with onset in infancy (SAVI). In an exemplary embodiment, the STING associated disease is a neurodegenerative disease, which is ischaemic brain injury, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, age-dependent macular degeneration, traumatic brain injury, or general neurodegeneration.

[0055] All publications and patent applications mentioned in this disclosure are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0056] No admission is made that any reference cited herein constitutes prior art. The discussion of the references states what their authors assert, and the Applicant reserves the right to challenge the accuracy and pertinence of the cited documents. It will be clearly understood that, although a number of information sources, including scientific journal articles, patent documents, and textbooks, are referred to herein; this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0057] The discussion of the general methods given herein is intended for illustrative purposes only. Other alternative methods and alternatives will be apparent to those of skill in the art upon review of this disclosure, and are to be included within the spirit and purview of this application.Attorney Docket No.: ARCI-002WO

[0058] Additional embodiments are disclosed in further detail in the following examples, which are provided by way of illustration and are not in any way intended to limit the scope of this disclosure or the claims. EXAMPLES

[0059] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, cell biology, biochemistry, nucleic acid chemistry, and immunology, which are well known to those skilled in the art. Such techniques are explained fully in the literature, such as Sambrook, J., & Russell, D. W. (2012). Molecular Cloning: A Laboratory Manual (4th ed.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory and Sambrook, J., & Russel, D. W. (2001). Molecular Cloning: A Laboratory Manual (3rd ed.). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory (jointly referred to herein as “Sambrook”); Ausubel, F. M. (1987). Current Protocols in Molecular Biology. New York, NY: Wiley (including supplements through 2014); Bollag, D. M. et al. (1996). Protein Methods. New York, NY: Wiley-Liss; Huang, L. et al. (2005). Nonviral Vectors for Gene Therapy. San Diego: Academic Press; Kaplitt, M. G. et al. (1995). Viral Vectors: Gene Therapy and Neuroscience Applications. San Diego, CA: Academic Press; Lefkovits, I. (1997). The Immunology Methods Manual: The Comprehensive Sourcebook of Techniques. San Diego, CA: Academic Press; Doyle, A. et al. (1998). Cell and Tissue Culture: Laboratory Procedures in Biotechnology. New York, NY: Wiley; Mullis, K. B., Ferré, F. & Gibbs, R. (1994). PCR: The Polymerase Chain Reaction. Boston: Birkhauser Publisher; Greenfield, E. A. (2014). Antibodies: A Laboratory Manual (2nd ed.). New York, NY: Cold Spring Harbor Laboratory Press; Beaucage, S. L. et al. (2000). Current Protocols in Nucleic Acid Chemistry. New York, NY: Wiley, (including supplements through 2014); and Makrides, S. C. (2003). Gene Transfer and Expression in Mammalian Cells. Amsterdam, NL: Elsevier Sciences B.V., the disclosures of which are incorporated herein by reference.

[0060] Additional embodiments are disclosed in further detail in the following examples, which are provided by way of illustration and are not in any way intended to limit the scope of this disclosure or the claims.Attorney Docket No.: ARCI-002WO EXAMPLE 1 Materials and Methods Peptide Inhibitor (“PI”) Synthesis

[0061] Peptide inhibitors were synthesized using a Syro automated peptide synthesizer, with standard automated solid-phase peptide synthesis protocols, as outlined in FIG 1. PIs were synthesized using suitably protected, all canonical amino acids in a C^N stepwise fashion and collected immobilized on a resin support. The C-terminal amino acid was an orthogonally protected cysteine to aid in cyclization of the peptide.

[0062] PI sequences are provided in Table 1: Table 1 Peptide Inhibitor Sequence (C^N)SEQ ID NOPI 1 YWWKNRNILWVSC 1PI Cyclization

[0063] Cyclization of the individual PI was then performed as outlined for PI 2 in FIG 2 (SEQ ID NO:5, below). The immobilized peptide on resin was subjected to basic deprotection, and the C-terminal cysteine sulfhydryl is deprotected. The free N-terminus is functionalized with a chloroacetyl group. Cyclization was allowed to occur under basic conditions. The peptide was then cleaved from the resin and all side chain groups were deprotected. The resultant peptide was purified by HPLC.

[0064] The representative final structure of a cyclic PI is provided, with N-terminal tyrosine and C-terminal cysteine shown in full, and intervening amino acids represented with their one-letter symbols. PG = protecting group; MMT = monomethoxytrityl, the protecting group for the cysteine sulfhydryl that will perform the cyclization. Surface Plasmon Resonance (SPR) Affinities

[0065] Surface plasmon resonance (SPR) was performed to evaluate the affinities of the cyclic PI. Biotinylated STING used for the selection was constituted in buffer containing cGAMP and immobilized using the Biotin CAPture kit on a Biacore T200 instrument. Cyclic PIs were constituted in buffer containing cGAMP and flowed over the surface in a dilution series. The fitted Kd value for PI 2 was 0.36 nM.Attorney Docket No.: ARCI-002WO Blue-Native PAGE experiments

[0066] Blue-Native PAGE experiments were performed using purified PIs of the invention. This measured the extent of STING oligomerization in response to cGAMP stimulation. Human STING was expressed in HEK293T, a cell line which does not express STING endogenously but contains all the components required for its downstream signaling. HEK293T cells were transfected to express wild-type human STING for 20 h, and PI 2 was used to treat cells at 1 µM for 1 h, followed by stimulation with 50 µM cGAMP for 30 min. Results are shown below in FIG 3 (Veh = Vehicle). Peptide 2 inhibited oligomerization induced by cGAMP. PI 2 strikingly restored the presence of a low molecular weight dimer associated with unstimulated STING, even in the presence of cGAMP. Assessment of STING oligomerization by PI 2

[0067] PI 2 was next evaluated in a Blue-Native assay using limited dilution series and against R284S, a mutant of STING that was associated with the autoimmune disease SAVI and also exhibited STING oligomerization in the absence of cGAMP stimuli. The cells were stimulated similarly to the Blue-Native assay above, except cells expressing R284S STING were not stimulated. A dose-dependent reduction in STING oligomerization was observed in both stimulated wild-type STING and unstimulated R284S STING as shown in FIG 4. This indicates that PI 2 inhibited human STING oligomerization. Assessment of STING oligomerization in PBMC by PI 2

[0068] The ability of PI 2 to inhibit signaling of endogenous STING in patient samples was next evaluated by utilizing RT-qPCR. Signal inhibition was monitored via the expression of the following human-specific interferon-stimulated genes (ISGs): C-X-C motif chemokine ligand 10 (CXCL10); oligoadenylate synthase (OAS); interferon induced protein with tetratricopeptide repeats 1 (IFIT1); interferon induced protein with tetratricopeptide repeats 2 (IFIT2); and interferon induced protein with tetratricopeptide repeats 3 (IFIT3). Peripheral blood mononuclear cells (PBMCs) were isolated from four independent donors (deidentified and numbered according to their storage in the laboratory, 2.5–3 x 106per condition). These PBMCs were treated with vehicle only or 1 µM PI 2 for 1 h, then stimulated with 50 µM cGAMP for 18 h. Cells were harvested and RNA extraction was performed, before RT- qPCR with probes directed against the indicated ISGs. For individual samples, transcript levels were normalized against actin as the housekeeping gene, and the fold change as reported was normalized to parallel samples of cells treated with vehicle, but not stimulated with cGAMP.Attorney Docket No.: ARCI-002WO

[0069] A summary of the data is provided in Table 2. Table 2 ISG Donor 2 Donor 3 Donor 5 Donor 13 Veh PI 2 Veh PI 2 Veh PI 2 Veh PI 2

[0070] , to vehicle controls against cGAMP stimulation. This suggested PI 2 functioned as a potent STING inhibitor. Additional PI cyclization conditions

[0071] The PIs described herein can be cyclized as described previously herein (e.g. in the Examples section). The PIs can also be cyclized utilizing other methods known to one of skill in the art. Exemplary cyclization methods include chemical methods, such as direct backbone cyclization, native chemical ligation, aldehyde-based ligations, bioorthogonal reactions, disulphide formation), enzymatic methods, such as subtiligase variants, sortases, asparaginyl endopeptidases, transglutaminases, non-ribosomal peptide synthetases), and protein tag methods, such as inteins, engineered protein domains for isopeptide bond formation. In some embodiments, peptide cyclization methods include side chain-to-side chain cyclization, head-to-tail cyclization, tail-to-side cyclization and head-to-side cyclization. The amino acids at position X1and X13may be any amino acids compatible with a given cyclization method. X1and X13may be any amino acid, including any non-natural amino acids known to one of skill in the art, that can cyclize to each other via a cyclization reaction. In an exemplary embodiment, N-to-C cyclization is utilized, such as when X1has the structure: represents connection to the remainder ofembodiment, click chemistryAttorney Docket No.: ARCI-002WO cyclization is utilized, such as when X13has the X1hasthe structure propargyl, and the alkyne and azide moieties arecycloaddition to afford the linkage such that X1an exemplarythe structure , where R3optionally cyclized using Cu(I)-mediated cycloaddition such that X1is H. In an– OCH2CH2OH and R3in X1is –H, and cyclization is achieved under enzyme-mediated conditions with an enzyme such as Survival Protein E (SurE) and WolJ such that X1isAttorney Docket No.: ARCI-002WO . In an exemplary embodiment, Pictet-Spengler ligation isutilized, such as i.e., X1is tyrosine orcyclization is achieved under enzyme-mediated conditions with an enzyme such as strictosidine synthase, such that when X1is tyrosineor when X1is tryptophan.EXAMPLE 2 Saturation Mutagenesis Studies

[0072] The mRNA library was prepared as previously described in Yamagishi et al., Chemistry and Biology 2011. Briefly, the initial puromycin-ligated library was prepared at 150 μL scale by in vitro translation in the presence of 250 μM of the appropriate initiator tRNA (ClAcD / LTyr-tRNAfMetCAU) at 37°C for 30 min, then incubated 25°C for 12 min. 30 μL of 100 mM EDTA (pH 8.0) was added, and the reaction mixture allowed to cyclize at 37°C for 30 min. The mixture was then reverse transcribed for 1 h at 42ºC. Separately, biotinylated STING was diluted in TBS-T and loaded onto Dynabeads M280 streptavidin magnetic beads at a ratio of 300 pmol protein to 150 μL beads by incubation at 4ºC for 10 min, followed by blocking with 250 μM biotin added at one tenth of the total volume, and incubating at 4ºC for a further 10 min. The beads were then washed three times in TBS-TAttorney Docket No.: ARCI-002WO containing 50 μM cGAMP before use. The negative selection was performed on beads with biotinylated STING R284E, and washed in TBS-T without cGAMP. Following preparation of the beads, the reverse-transcribed library was added and rotated at 4ºC for 30 min. The supernatant was then removed and the beads washed with ice-cold TBS-T. The beads containing bound cDNA were then eluted with 1X PCR reaction buffer for 5 min at 95ºC, then the eluate was collected and sampled for quantitation with RT-qPCR, then amplified by PCR, purified and transcribed into mRNA overnight. The resultant mRNA library was then ligated with puromycin and cycled into the next selection round at 2.5 μL scale. Beginning from the second round, the reverse-transcribed cDNA was first negatively selected by three successive incubation steps with samples of streptavidin-only beads with half the streptavidin blocked by biotin, before the final supernatant was input into selection with target.

[0073] mRNA selection with saturation mutagenesis was similarly carried out. The initial library was prepared using the original ET6 sequence (YWNSQHHILWWTC [SEQ ID NO:2]) linked to a GGSG (SEQ ID NO:6) linker and an HA epitope tag (YPYDVPDYA [SEQ ID NO:7]), and amplified using primers that individually allowed each position of the ET6 sequence (except the initial and final residues) to be varied into NNK codons coding for each of the other 19 amino acids. The library was then translated, cyclized and reverse transcribed as described above, then incubated with anti-HA magnetic beads to specifically enrich for ET6 mutation sequences. Following washes to remove non-specific binders, the library was eluted using HA peptide, then immobilized onto streptavidin beads for selection against STING as described above.

[0074] After selection, both eluted libraries from both the positive selection (containing enriched hits) and control selection were analyzed by NGS using MiSeq, which produced a total count of each enriched sequence. From the sequencing results, a sequence count was obtained from the positive selection (pep count binding) and control selection (pep count non-binding) ,and respectively divided by the total number of reads obtained in each sequencing run to obtain normalized counts. The Y score is calculated: pep count binding normalized / pep count non-binding normalized. The peptides are ranked by Y score, and then manually curated to remove peptides whose pep count binding was low (<500) to obtain the top 80 hits. These were aligned on JalView for visualization.Attorney Docket No.: ARCI-002WO

[0075] Additional PI sequences of the invention are provided in Table 3: Table 3 Peptide Inhibitor Sequence (C^N) SEQ ID NO Y score PI 5 YWNSQIHILWWTC 8 +++Attorney Docket No.: ARCI-002WO Peptide Inhibitor Sequence (C^N) SEQ ID NO Y score PI 40 YWNSLHHILWWTC 43 ++Attorney Docket No.: ARCI-002WO Peptide Inhibitor Sequence (C^N) SEQ ID NO Y score PI 77 YWNCQHHILWWTC 80 + Y Sc

[0076] In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0077] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use ofAttorney Docket No.: ARCI-002WO definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0078] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0079] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles.Attorney Docket No.: ARCI-002WO Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0080] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

[0081] Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims.

[0082] The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims. In the claims, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is expressly defined as being invoked for a limitation in the claim only when the exact phrase "means for" or the exact phrase "step for" is recited at the beginning of such limitation in the claim; if such exact phrase is not used in a limitation in the claim, then 35 U.S.C. § 112 (f) or 35 U.S.C. §112(6) is not invoked.

Claims

Attorney Docket No.: ARCI-002WO WHAT IS CLAIMED IS:

1. A peptide, or a salt thereof, comprising a structure of Formula (I): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13(I) wherein X1is a natural amino acid or an unnatural amino acid; X2is tryptophan or aspartic acid; X3is a natural amino acid or an unnatural amino acid; X4is a natural amino acid or an unnatural amino acid; X5is a natural amino acid or an unnatural amino acid; X6is a natural amino acid or an unnatural amino acid; X7is a natural amino acid or an unnatural amino acid; X8is isoleucine, phenylalanine, or tryptophan; X9is leucine, isoleucine, phenylalanine, tryptophan, or glycine; X10is isoleucine, tryptophan, or threonine; X11is isoleucine, phenylalanine, cysteine, valine, tryptophan, or leucine; X12is a natural amino acid or an unnatural amino acid; X13is a natural amino acid or an unnatural amino acid; wherein X1and X13are optionally covalently attached.

2. The peptide, or a salt thereof, of claim 1, wherein X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, valine, leucine, methionine, arginine, histidine, alanine, threonine, serine, lysine, cysteine, glycine, or glutamine.

3. The peptide, or a salt thereof, of claim 1, wherein X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, valine, leucine, methionine, arginine, histidine, alanine, or threonine.

4. The peptide, or a salt thereof, of claim 1, wherein X3is arginine, histidine, alanine, or threonine.

5. The peptide, or a salt thereof, of claim 1, wherein X3is leucine or methionine.

6. The peptide, or a salt thereof, of claim 1, wherein X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, or valine.Attorney Docket No.: ARCI-002WO 7. The peptide, or a salt thereof, of claim 1, wherein X3is asparagine.

8. The peptide, or a salt thereof, of claim 1, wherein X4is cysteine, alanine, arginine, methionine, leucine, lysine, phenylalanine, serine, valine, tyrosine, isoleucine, tryptophan, or histidine.

9. The peptide, or a salt thereof, of claim 1, wherein X4is cysteine, alanine, arginine, methionine, leucine, phenylalanine, serine, valine, tyrosine, isoleucine, tryptophan, or histidine.

10. The peptide, or a salt thereof, of claim 1, wherein X4is cysteine, alanine, arginine, methionine, leucine, or histidine.

11. The peptide, or a salt thereof, of claim 1, wherein X4is valine, tyrosine, isoleucine, or tryptophan.

12. The peptide, or a salt thereof, of claim 1, wherein X4is phenylalanine.

13. The peptide, or a salt thereof, of claim 1, wherein X4is serine.

14. The peptide, or a salt thereof, of claim 1, wherein X5is asparagine, lysine, cysteine, alanine, serine, threonine, histidine, methionine, arginine, glutamine, tryptophan, phenylalanine, isoleucine, tyrosine, valine, leucine, or proline.

15. The peptide, or a salt thereof, of claim 1, wherein X5is lysine, cysteine, alanine, serine, threonine, histidine, methionine, arginine, glutamine, tryptophan, phenylalanine, isoleucine, tyrosine, valine, or leucine.

16. The peptide, or a salt thereof, of claim 1, wherein X5is lysine, cysteine, alanine, serine, threonine, histidine, methionine, or arginine.

17. The peptide, or a salt thereof, of claim 1, wherein X5is tryptophan, phenylalanine, isoleucine, tyrosine, valine, or leucine.

18. The peptide, or a salt thereof, of claim 1, wherein X5is glutamine.

19. The peptide, or a salt thereof, of claim 1, wherein X6is arginine, isoleucine, valine, leucine, histidine, tyrosine, tryptophan, threonine, or cysteine.Attorney Docket No.: ARCI-002WO 20. The peptide, or a salt thereof, of claim 1, wherein X6is isoleucine, valine, leucine, histidine, tyrosine, tryptophan, threonine, or cysteine.

21. The peptide, or a salt thereof, of claim 1, wherein X6is threonine or cysteine.

22. The peptide, or a salt thereof, of claim 1, wherein X6is tyrosine.

23. The peptide, or a salt thereof, of claim 1, wherein X6is isoleucine, valine, leucine, histidine, or tryptophan.

24. The peptide, or a salt thereof, of claim 1, wherein X6is histidine.

25. The peptide, or a salt thereof, of claim 1, wherein X7is asparagine, histidine, phenylalanine, isoleucine, tryptophan, arginine, tyrosine, leucine, threonine, alanine, methionine, or valine.

26. The peptide, or a salt thereof, of claim 1, wherein X7is histidine, phenylalanine, isoleucine, tryptophan, tyrosine, leucine, threonine, alanine, methionine, or valine.

27. The peptide, or a salt thereof, of claim 1, wherein X7is threonine, alanine, or methionine.

28. The peptide, or a salt thereof, of claim 1, wherein X7is valine.

29. The peptide, or a salt thereof, of claim 1, wherein X7is histidine, phenylalanine, isoleucine, tryptophan, tyrosine, or leucine.

30. The peptide, or a salt thereof, of claim 1, wherein X7is histidine.

31. The peptide, or a salt thereof, of claim 1, wherein X8is phenylalanine or tryptophan.

32. The peptide, or a salt thereof, of claim 1, wherein X8is isoleucine.

33. The peptide, or a salt thereof, of claim 1, wherein X9is leucine, isoleucine, phenylalanine, or tryptophan.

34. The peptide, or a salt thereof, of claim 1, wherein X9is isoleucine, phenylalanine, or tryptophan.

35. The peptide, or a salt thereof, of claim 1, wherein X9is leucine.Attorney Docket No.: ARCI-002WO 36. The peptide, or a salt thereof, of claim 1, wherein X10is isoleucine.

37. The peptide, or a salt thereof, of claim 1, wherein X10is tryptophan.

38. The peptide, or a salt thereof, of claim 1, wherein X11is isoleucine, phenylalanine, or cysteine.

39. The peptide, or a salt thereof, of claim 1, wherein X11is tryptophan.

40. The peptide, or a salt thereof, of claim 1, wherein X12is isoleucine, phenylalanine, leucine, histidine, alanine, methionine, cysteine, arginine, serine, threonine, tryptophan, valine, or tyrosine.

41. The peptide, or a salt thereof, of claim 1, wherein X12is histidine, alanine, methionine, cysteine, arginine, or serine.

42. The peptide, or a salt thereof, of claim 1, wherein X12is leucine.

43. The peptide, or a salt thereof, of claim 1, wherein X12is isoleucine, phenylalanine, threonine, tryptophan, valine, or tyrosine.

44. The peptide, or a salt thereof, of claim 1, wherein X12is threonine.

45. The peptide, or a salt thereof, of claim 1, wherein X1is tyrosine.

46. The peptide, or a salt thereof, of claim 1, wherein X13is cysteine.

47. The peptide, or a salt thereof, of claim 1, wherein X1is tyrosine and X13is cysteine.

48. The peptide, or a salt thereof, of claim 1, wherein X1is cysteine and X13is tyrosine.

49. The peptide, or a salt thereof, of claim 1, wherein X1has a structure whichAttorney Docket No.: ARCI-002WO wherein represents a covalent attachment to X2; R4is H or a protecting group; and R3is H or C(O)CH2Cl; X13has a structure whereinor a protecting group; wherein R2and R3are optionally covalently attached whereinwherein .

50. Theor a X1has a structurewherein represents a covalent attachment to X2; R4is H or a protecting group; and R3is H or C(O)CH2Cl;Attorney Docket No.: ARCI-002WO X13has a structure which whereinto X12; R1is NH2; and R2is H or a protecting group; wherein R2and R3are covalently attached.

51. The peptide, or a salt thereof, of claim 1, wherein each of X1-X2, X2-X3, X3-X4, X4- X5, X5-X6, X6-X7, X7-X8, X8-X9, X9-X10, X10-X11, X11-X12, and X12-X13are covalently attached through an eupeptide bond.

52. The peptide, or a salt thereof, of claim 1, wherein X10is tryptophan and X11is tryptophan.

53. The peptide, or a salt thereof, of claim 1, wherein X9is leucine, X10is tryptophan, and X11is tryptophan.

54. The peptide, or a salt thereof, of claim 1, wherein X8is isoleucine, X9is leucine, X10is tryptophan, and X11is tryptophan.

55. The peptide, or a salt thereof, of claim 1, wherein X2is tryptophan, X8is isoleucine, X9is leucine, X10is tryptophan, and X11is tryptophan.

56. The peptide, or a salt thereof, of claim 1, wherein X2is tryptophan, X3is tryptophan, asparagine, phenylalanine, isoleucine, tyrosine, or valine, X4is phenylalanine or serine, X5is glutamine, X6is isoleucine, valine, leucine, or histidine, X7is histidine, phenylalanine, isoleucine, tryptophan, tyrosine, or leucine, X8is isoleucine, X9is leucine, X10is tryptophan, X11is tryptophan, and X12is threonine or valine.

57. The peptide, or a salt thereof, of claim 1, wherein X2is tryptophan, X3is asparagine, X4is serine, X5is glutamine, X6is histidine, X7is histidine, X8is isoleucine, X9is leucine, X10is tryptophan, X11is tryptophan, and X12is threonine.

58. The peptide, or a salt thereof, of claim 49, wherein R2and R3are covalently attached.Attorney Docket No.: ARCI-002WO 59. The peptide, or a salt thereof, of claim 58, wherein the R2and R3covalent attachment is through a cyclization condition described herein.

60. The peptide, or a salt thereof, of claim 58, wherein the X13-X1has a structure which is ** .

61. The peptide,and R4is H.

62. A pharmaceutical composition comprising: a) the peptide, or a pharmaceutically acceptable salt thereof, of any of claims 1-61; and b) one or more pharmaceutically acceptable excipients.

63. A method of inhibiting STING, comprising: contacting the STING with the peptide, or a salt thereof, of any of claims 1-61, or the pharmaceutical composition of claim 62, thereby inhibiting STING.

64. A method of treating a STING associated disease in a mammal, comprising: administering to the mammal in need of treatment thereof a therapeutically effective amount of the peptide, or a salt thereof, of any of claims 1-61, or the pharmaceutical composition of claim 62, thereby treating the STING associated disease.

65. The method of claim 64, wherein the STING associated disease is an autoimmune disease or a neurodegenerative disease.

66. The method of claim 64, wherein the STING associated disease is an autoimmune disease, which is lupus, multiple sclerosis, or STING-associated vasculopathy with onset in infancy (SAVI).Attorney Docket No.: ARCI-002WO 67. The method of claim 64, wherein the STING associated disease is a neurodegenerative disease, which is ischaemic brain injury, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, age-dependent macular degeneration, traumatic brain injury, or general neurodegeneration.

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