Use of MUC1 mimetic peptide inhibitors for inhibition of mucus secretion

Abstract

Disclosed herein are methods of decreasing mucus hypersecretion in the lungs comprising administering an effective amount of a MUC1 inhibitor to a subject in need thereof. In certain embodiments, the MUC1 inhibitor is the peptide GO-201, GO-203, or GO-203-2C. In certain embodiments, the subject is a human patient. In certain embodiments, the subject is diagnosed with rhinosinusitis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, or a respiratory syncytial virus (RSV) infection.

Description

[0001] USE OF MUC1 MIMETIC PEPTIDE INHIBITORS FOR INHIBITION OF MUCUS SECRETION

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 641,243 filed May 1, 2024. The entirety of this application is hereby incorporated by reference for all purposes.

[0004] INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED AS AN XML FILE VIA THE OFFICE ELECTRONIC FILING SYSTEM

[0005] The Sequence Listing associated with this application is provided in XML format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing is 24030PCT.xml. The XML file is 10,045 bytes, was created on April 30, 2025, and is being submitted electronically via the USPTO Patent Center.

[0006] BACKGROUND

[0007] Chronic exposure to cigarette smoke (CS) mediates pathological airway epithelial remodeling that ultimately leads to mucus hypersecretion, a hallmark of chronic airway diseases including chronic pulmonary obstructive disease (COPD) and emphysema. In the airways, CS promotes sustained activation of epidermal growth factor receptor (EGFR), resulting in goblet cell metaplasia (GCM) and persistent overexpression of the gel-forming mucin MUC5AC. Studies in the cancer arena demonstrate a role for MUC1 (a membrane-bound mucin) in promoting sustained EGFR activation, which results in cancer progression.

[0008] Kato et al. report MUC1 contributes to goblet cell metaplasia and MUC5AC expression in response to cigarette smoke in vivo. Am J Physiol Lung Cell Mol Physiol, 319: L82-L90, 2020.

[0009] Liu et al. report MUC1 attenuates neutrophilic airway inflammation in asthma by reducing NLRP3 inflammasome-mediated pyroptosis through the inhibition of the TLR4 / MyD88 / NF-KB pathway. Respiratory Research, 2023, 24:255.

[0010] Raina et al. report the MUC1 oncoprotein is aberrantly overexpressed in human breast cancers, and a MUC1 inhibitor, designated GO-201, that binds to the MUC1 cytoplasmic domain and blocks the formation of MUC1 oligomers in cells. Cancer Res, 2009, 69(12): 5133-5141. See also US Pat Nos, 8,524,669, 8,685,928, and 9,044,421. Uchida et al report inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in the treatment of breast cancer cells, and a MUC1-C inhibitor, GO-203, a cell penetrating peptide that blocks MUC1-C homodimerization. Cancer Biology & Therapy, 2013,14:2, 127-134.

[0011] Liegel et al. report a clinical trial of the MUC-1 inhibitor GO-203 -2C in acute myeloid leukemia. Blood, 2017, 130 (Suppl_l):2659.

[0012] References cited herein are not an admission of prior art.

[0013] SUMMARY

[0014] This disclosure relates to methods of decreasing mucus hypersecretion in the lungs comprising administering an effective amount of a MUC1 inhibitor to a subject in need thereof.

[0015] In certain embodiments, the MUC1 inhibitor is the peptide D-Arg-D-Arg- D-Arg-D-Arg- D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-Cys-Gln-Cys-Arg-Arg-Lys-Asn-Tyr-Gly-Gln-Leu-Asp-Ile- Phe-Pro (SEQ ID NO: 1) (GO-201) or D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg- D-Arg-D-Cys-D-Gln-D-Cys-D-Arg-D-Arg-D-Lys-D-Asn (SEQ ID NO: 2) (GO-203), or Acetyl- D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-[D-Cys-D-Gln-D-Cys]-D-Arg- D-Arg-D-Lys-D-Asn-NH2 (SEQ ID NO: 3) (Cys disulfide) (GO-203-2C).

[0016] In certain embodiments, the subject is a human patient. In certain embodiments, the subject is diagnosed with rhinosinusitis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, or respiratory syncytial virus (RSV) infection or other virus.

[0017] In certain embodiments, this disclosure relates to methods of treating or preventing chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis, asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome (ARDS), cystic fibrosis, or respiratory syncytial virus RSV infection comprising administering an effective amount of MUC1 inhibitors to a subject in need thereof. In certain embodiments, the MUC1 inhibitor is the peptide D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-Cys-Gln-Cys-Arg-Arg-Lys- Asn-Tyr-Gly-Gln-Leu-Asp-Ile-Phe-Pro (SEQ ID NO: 1) (GO-201) or D-Arg-D-Arg-D-Arg-D- Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Cys-D-Gln-D-Cys-D-Arg-D-Arg-D-Lys-D-Asn (SEQ ID NO: 2) (GO-203), or Acetyl-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg- D-Arg-[D-Cys-D-Gln-D-Cys]-D-Arg-D-Arg-D-Lys-D-Asn-NH2 (SEQ ID NO: 3) (N-terminal acetylated, C-terminal amide, with Cys disulfide) (GO-203-2C). In certain embodiments, the subject is a human patient.

[0018] In certain embodiments, this disclosure relates to methods of treating or preventing chronic rhinosinusitis comprising administering an effective amount of MUC1 inhibitors to a subject in need thereof. In certain embodiments, the MUC1 inhibitor is the peptide D-Arg-D-Arg- D-Arg- D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-Cys-Gln-Cys-Arg-Arg-Lys-Asn-Tyr-Gly-Gln-Leu- Asp-Ile-Phe-Pro (SEQ ID NO: 1) (GO-201) orD-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg- D-Arg-D-Arg-D-Cys-D-Gln-D-Cys-D-Arg-D-Arg-D-Lys-D-Asn (SEQ ID NO: 2) (GO-203), or Acetyl-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-[D-Cys-D-Gln-D-Cys]- D-Arg-D-Arg-D-Lys-D-Asn-NH2 (SEQ ID NO: 3) (N-terminal acetylated, C-terminal amide, with Cys disulfide) (GO-203-2C). In certain embodiments, the subject is a human patient.

[0019] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0020] Figure 1 shows data indicating GO-201 reduces MUC5AC mRNA levels. NCI-H292 cells were serum starved (FBS 1% in RPMI media) for 4h, pretreated with GO-201 for 30 min followed by treatment with EGF (50 ng / ml) for 24h. MUC5AC gene expression was determined by RT- PCR, normalized to GAPDH (n=4). Data shown as fold change compared to control (untreated).

[0021] DETAILED DESCRIPTION

[0022] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims or as amended during prosecution.

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

[0024] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0025] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

[0026] An "embodiment" of this disclosure refers to an example and infers that the example is not necessarily limited to the example. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

[0027] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

[0028] As used herein, the term "about" is synonymous with the term "approximately." Illustratively, the use of the term "about" indicates that a value includes values slightly outside the cited values. Variation may be due to conditions such as experimental error, manufacturing tolerances, variations in equilibrium conditions, and the like. In some embodiments, the term "about" includes the cited value plus or minus 5% or 10%. In all cases, where the term "about" has been used to describe a value, it should be appreciated that this disclosure also supports the exact value.

[0029] As used in this disclosure and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") have the meaning ascribed to them in U.S. Patent law in that they are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. "Consisting essentially of' or "consists of' or the like, have the meaning ascribed to them in U.S. Patent law in that when applied to methods and compositions encompassed by the present disclosure refers to the idea of excluding certain prior art element(s) as an inventive feature of a claim, but which may contain additional composition components or method steps, etc., that do not materially affect the basic and novel character! stic(s) of the compositions or methods, compared to those of the corresponding compositions or methods disclosed herein.

[0030] The term “comprising” in reference to a peptide having an amino acid sequence refers a peptide that may contain additional N-terminal (amine end) or C-terminal (carboxylic acid end) amino acids, i.e., the term is intended to include the amino acid sequence within a larger peptide. The term “consisting of’ in reference to a peptide having an amino acid sequence refers a peptide having the exact number of amino acids in the sequence and not more or having not more than a range of amino acids expressly specified in the claim. In certain embodiments, the disclosure contemplates that the “N-terminus of a peptide consists of an amino acid sequence,” which refers to the N-terminus of the peptide having the exact number of amino acids in the sequence and not more or having not more than a range of amino acids specified in the claim; however, the C- terminus may be connected to additional amino acids, e.g., as part of a larger peptide. Similarly, the disclosure contemplates that the “C-terminus of a peptide consists of an amino acid sequence,” which refers to the C-terminus of the peptide having the exact number of amino acids in the sequence and not more or having not more than a range of amino acids specified in the claim; however, the N-terminus may be connected to additional amino acids, e.g., as part of a larger peptide. In certain embodiments, the disclosure contemplates the enantiomers of N-terminus and C-terminus of the peptides.

[0031] The terms "protein" and "peptide" refer to compounds comprising amino acids joined via peptide bonds and are used interchangeably. As used herein, where "amino acid sequence" is recited herein to refer to an amino acid sequence of a protein molecule. An "amino acid sequence" can be deduced from the nucleic acid sequence encoding the protein. Furthermore, unless the context demands otherwise, the term "peptide" and "polypeptide" and "protein" are used interchangeably to refer to amino acids in which the amino acid residues are linked by covalent peptide bonds or alternatively (where post-translational processing has removed an internal segment) by covalent disulfide bonds, etc. The ammo acid chains can be of any length and comprise at least three amino acids, they can include domains of proteins or full-length proteins. Unless otherwise stated the terms peptide, polypeptide, and protein also encompass various modified forms thereof, including but not limited to glycosylated forms, phosphorylated forms, etc.

[0032] "Subject" refers to any animal, preferably a human patient, livestock, rodent, monkey, or domestic pet. In certain embodiments, the subject is a human subject 2, 12, 16, or 20 years old or older. In certain embodiments, the subject is a human subject 2, 12, or 15 years old or older or less than 2, 12, or 16 years old. In certain embodiments, the subject is a human subject 55 or 65 years old or older. In certain embodiments, the subject is a human subject greater than 55, 60, 65, or 70 years of age. In certain embodiments, the subject is an infant, e.g., from one month to two years of age. In certain embodiments, the subject is a human subject such as a child, e.g., from two to twelve years of age. In certain embodiments, the subject is a human subject such as an adolescent, e.g., from twelve to sixteen years of age. In certain embodiments, the subject is a human subject sixteen years of age or older.

[0033] As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatment that merely reduces symptoms, and / or delays disease progression.

[0034] As used herein, the term "in combination with," when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to a subject or human patient prior to, concurrent with, or subsequent to each other such that they are contained / circulating in the patient at the same time, e.g., considering half-lives of the agents.

[0035] Rhinosinusitis, also referred to as “sinusitis,” refers to a condition where paranasal sinuses become inflamed and often swollen. Viral or bacterial infections typically cause rhinosinusitis; however, rhinosinusitis can also be a result of growths in the sinuses or other conditions (e.g., allergies). Symptoms typically include obstructed nasal passages, pain, tenderness, runny nose, drainage down the back of the throat (post-nasal drip), and / or swelling around eyes, cheeks, nose, forehead. Acute sinusitis is often short-lasting sinusitis; however, chronic sinusitis, also referred to as longer-lasting sinusitis, often results in bacterial infections necessitating antibiotic therapies.

[0036] “Chronic obstructive pulmonary disease (COPD)” refers to a progressive airflow limitation caused by an abnormal inflammatory reaction to the inhalation of particles such as cigarette smoke or asbestos. Doctors diagnose COPD by observing symptoms of a patient, evaluating life-style choices such as smoking and occupation, and conducting spirometry tests to measure airflow of a patient. A diagnostic parameter of COPD is the observation of a declining forced expiratory volume in 1 second (FEV1) as measured by spirometry. Lung function declines more rapidly than normal, leading to an accelerated limitation in physical performance (poor exercise tolerance) and dyspnea. An increased rate of decline in FEV1 is typically observed (less than 20 ml / year).

[0037] "Bronchiectasis" refers to a condition where the walls of the bronchi are thickened which can result in periodic flare-ups of breathing difficulties, also referred to as exacerbations. Cylindrical (tubular) bronchiectasis is characterized by cylinder-shaped bronchi / bronchioles. Cylindrical bronchiectasis is a morphologic type of bronchiectasis where there is smooth uniform enlargement of bronchi with loss of the normal distal tapering of the airways without focal outpouchings. Bronchial dilatation is typically evaluated in relation to the accompanying pulmonary artery. A broncho to arterial ratio greater than 1 : 1 is typically considered abnormal. Normal bronchi are narrower in diameter the further they are from the lung hilum. Lack of normal bronchial tapering over 2 cm in length, distal from an airway bifurcation, is a sign of bronchiectasis. Varicose bronchiectasis bronchi are irregular, and the airways may be wide or constricted. In cystic bronchiectasis, cysts can occur in the subpleural areas, where they typically represent paraseptal emphysema, bullae, or honeycombing. Bronchiectasis is typically a chronic respiratory condition, characterized by frequent cough and shortness of breath due to a range of conditions that include inherited mucociliary defects, inhalational airway injury, immunodeficiency states and prior respiratory infections. Bronchiectasis is characterized as a thickening and dilation of the walls of the bronchi from inflammation, infection, or other etiologies which result in the inability to clear mucus from the airway. Affected individuals are then more susceptible to repeated lung infections.

[0038] Bronchiectasis is commonly found in individuals with cystic fibrosis. Cystic fibrosis is typically diagnosed in human patients having one or more mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF patients are typically diagnosed with persistent pulmonary infections, elevated sweat chloride, and pancreatic insufficiency. In certain embodiments, elevated sweat chloride is in a concentration above 30 or 60 millimoles per liter (mEq / L).

[0039] Asthma is a chronic condition where airways become inflamed and narrow, leading to excess mucus production, which can trigger coughing and difficulty breathing. Chronic Bronchitis is a type of chronic obstructive pulmonary disease where the bronchial tubes become inflamed and produce excess of mucus leading to coughing and difficulty clearing the airways.

[0040] Respiratory Syncytial Virus (RSV) is a common virus that can cause severe inflammation and mucus overproduction in infants, leading to serious respiratory issues.

[0041] Methods of Use

[0042] This disclosure relates to methods of decreasing mucus hypersecretion in the lungs comprising administering an effective amount of MUC1 inhibitors to a subject in need thereof. In certain embodiments, MUC1 inhibitor is the peptide D-Arg-D-Arg- D-Arg-D-Arg-D-Arg-D-Arg- D-Arg-D-Arg-D-Arg-Cys-Gln-Cys-Arg-Arg-Lys-Asn-Tyr-Gly-Gln-Leu-Asp-Ile-Phe-Pro (SEQ ID NO: 1) (GO-201) or D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Cys- D-Gln-D-Cys-D-Arg-D-Arg-D-Lys-D-Asn (SEQ ID NO: 2) (GO-203), or Acetyl-D-Arg-D-Arg- D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-[D-Cys-D-Gln-D-Cys]-D-Arg-D-Arg-D-Lys- D-Asn-NH2 (SEQ ID NO: 3) (Cys disulfide) (GO-203-2C). In certain embodiments, the subject is a human patient. In certain embodiments, the subject is diagnosed with chronic obstructive pulmonary disease (COPD), rhinosinusitis, chronic rhinosinusitis, bronchiectasis, or cystic fibrosis (CF).

[0043] In certain embodiments, this disclosure relates to methods of treating or preventing chronic obstructive pulmonary disease (COPD), comprising administering an effective amount of MUC1 inhibitors to a subject in need thereof. In certain embodiments, the MUC1 inhibitor is the peptide D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-Cys-Gln-Cys-Arg-Arg-Lys- Asn-Tyr-Gly-Gln-Leu-Asp-Ile-Phe-Pro (SEQ ID NO: 1) (GO-201) or D-Arg-D-Arg-D-Arg-D- Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Cys-D-Gln-D-Cys-D-Arg-D-Arg-D-Lys-D-Asn (SEQ ID NO: 2) (GO-203), or Acetyl-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg- D-Arg-[D-Cys-D-Gln-D-Cys]-D-Arg-D-Arg-D-Lys-D-Asn-NH2 (SEQ ID NO: 3) (Cys disulfide) (GO-203-2C). In certain embodiments, the subject is a human patient.

[0044] In certain embodiments, this disclosure relates to methods of treating or preventing chronic rhinosinusitis comprising administering an effective amount of a MUC1 inhibitor to a subject in need thereof. In certain embodiments, the MUC1 inhibitor is the peptide D-Arg-D-Arg- D-Arg- D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-Cys-Gln-Cys-Arg-Arg-Lys-Asn-Tyr-Gly-Gln-Leu- Asp-Tle-Phe-Pro (SEQ ID NO: 1) (GO-201) or D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg- D-Arg-D-Arg-D-Cys-D-Gln-D-Cys-D-Arg-D-Arg-D-Lys-D-Asn (SEQ ID NO: 2) (GO-203), or Acetyl-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-[D-Cys-D-Gln-D-Cys]- D-Arg-D-Arg-D-Lys-D-Asn-NH2 (SEQ ID NO: 3) (Cys disulfide) (GO-203-2C). In certain embodiments, the subject is a human patient.

[0045] In certain embodiments, administration is by a nebulizer. In certain embodiments, the nebulizer is a jet nebulizer driven by compressed air. In certain embodiments, the nebulizer is an ultrasonic nebulizer having a piezoelectric transducer for creating droplets from a liquid reservoir. In certain embodiments, the nebulizer is vibrating mesh nebulizer having perforated membranes actuated by an annular piezo element to vibrate. In certain embodiments, administration is a pressurized or unpressurized inhaler. In certain embodiments, administration is a metered-dose inhaler.

[0046] In certain embodiments, the subject is diagnosed with a bacterial infection.

[0047] In certain embodiments, the MUC1 inhibitor is a peptide administered in combination with a bronchodilator.

[0048] In certain embodiments, the peptide is administered in combination with nintedanib.

[0049] In certain embodiments, the peptide is administered in combination with pirfenidone.

[0050] In certain embodiments, the peptide is administered in combination with an antiinflammatory agent.

[0051] In certain embodiments, the peptide is administered in combination with an antibiotic agent. Suitable antibiotics include, without limitation, such as 2,4-diaminopyrimidines, including baquiloprim, brodimoprim, iclaprim, ormetoprim, pyrimethamine, tetroxoprim, trimethoprim; aminocoumarins including novobiocin; aminocyclitols including spectinomycin; aminoglycosides including amikacin, apramycin, arbekacin, bekanamycin, butirosin, dibekacin, dihydrostreptomycin, etimicin, fortimicins, astromicin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, micronomicin, neomycin, netilmicin, paromomycin, plazomicin, ribostamycin, sisomicin, streptomycin, tobramycin; aminomethylcyclines including omadacycline; amphenicols including azidamfenicol, chloramphenicol, florfenicol, thi amphenicol; ansamycins including rifabutin, rifampicin, rifapentine, rifaximin; antitubercular agents including cycloserine, delamanid, ethambutol, ethionamide, morinamide, protionamide, pyrazinamide, terizidone, thioacetazone; bacteriocins, including nisin; lactam carbapenems including loracarbef biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem, panipenem, razupenem, sulopenem, tebipenem, tomopenem; lactam cephalosporins including cefacetrile, cefaclor, cefadroxil, cefalexin, cefalonium, cefaloridine, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefcapene, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotiam, cefovecin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftizoxime, ceftobiprole, ceftolozane, ceftriaxone, cefuroxime, cefuzonam; lactam cephamycins including cefbuperazone, cefmetazole, cefotetan, cefoxitin; lactam monobactams including aztreonam, carumonam, tigemonam; lactam oxacephems including flomoxef, latamoxef, moxalactam; lactam penicillins including amdinocillin, amoxicillin, ampicillin, apalcillin, azidocillin, azlocillin, bacampicillin, carbenicillin, ciclacillin, clemizole penicillin, cioxacillin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin, mecillinam, metampicillin, methicillin sodium, mezlocillin, nafcillin, oxacillin, penamecillin, penethamate hydroiodide, penicillin G, penicillin G benzathine, penicillin G procaine, penicillin N, penicillin O, penicillin V, phenethicillin potassium, piperacillin, pivampicillin, pivmecillinam, propicillin, quinacillin, sultamicillin, talampicillin, temocillin, ticarcillin; lactam in combination with lactamase inhibitors including avibactam, clavulanic acid, relebactam, sulbactam, tazobactam, vaborbactam, zidebactam; bicyclomycins including bicozamycin; bis-benzimidazoles including ridinilazole; cyclic esters including fosfomycin; fluoroquinolones including avarofloxacin, balofloxacin, besifloxacin, cinoxacin, ciprofloxacin, clinafloxacin, danofloxacin, delafloxacin, difloxacin, enoxacin, enrofloxacin, finafloxacin, fleroxacin, flumequine, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, marbofloxacin, miloxacin, moxifloxacin, nadifloxacin, norfloxacin, ofloxacin, orbifloxacin, pazufloxacin, pefloxacin, pradofloxacin, prulifloxacin, rosoxacin, rufloxacin, sarafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin, zabofloxacin; fusidane-type including helvolic acid, fusidic acid and cephalosporin; glycolipodepsipeptides including ramoplanin; glycopeptides including avoparcin, dalbavancin, norvancomycin, oritavancin, teicoplanin, telavancin, vancomycin; glycylcyclines including tigecycline; lincosamides including clindamycin, lincomycin, pirlimycin; lipopeptides including daptomycin, surotomycin; macrolides, including azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, fidaxomicin, flurithromycin, gamithromycin, josamycin, kitasamycin, leucomycin, miocamycin, oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin, solithromycin, spiramycin, telithromycin, tildipirosin, tilmicosin, troleandomycin, tulathromycin, tylosin, tylvalosin; nitrofurans including furaltadone, furazidin, furazolidone, nifuroxazide, nifurtoinol, nifurzide, nitrofural, nitrofurantoin, nitrofurazone; nitroimidazoles, including dimetridazole, metronidazole, ornidazole, ronidazole, secnidazole, tinidazole; oligosaccharides including avilamycin, everninomicin; polymyxins including polymyxin E (colistin), polymyxin B; polypeptides including amphomycin, bacitracin, capreomycin, enduracidin, enramycin, gramicidin(s), ristocetin, tuberactinomycin, tyrocidine, tyrothricin, viomycin; pseudomonic acids including mupirocin; quinoxalines including carbadox, olaquindox; sulfonamides including acetyl sulfamethoxypyrazine, chloramine-B, chloramine-T, dichloramine T, mafenide, sulfacetamide, sulfadiazine, sulfadimidine, sulfamethazine, sulfamethizole, sulfapyridine, sulfathiazole, sulfisomidine, sulfisoxazole; sulfones including dapsone sodium, sulfanilic acid; tetracyclines including chlortetracycline, clomocycline, demeclocycline, doxycycline, lymecycline, meclocycline, methacycline, minocycline, oxytetracycline, rolitetracycline, tetracycline; triazaacenaphthylenes including gepotidacin, or any combination thereof.

[0052] In certain embodiments, this disclosure relates to treating a subject by inhalation to the lung. In certain embodiments, administration is by inhalation of an aerosol in the pulmonary airway. In certain embodiments, administration is by inhalation through the mouth and / or nose.

[0053] In certain embodiments, administration is by a metered-dose inhaler. In certain embodiments, administration is by a single or multiple dose dry powder inhaler. In certain embodiments, administration is by a nebulizer. In certain embodiments, administration is by a jet nebulizer driven by compressed air. In certain embodiments, the nebulizer is an ultrasonic nebulizer having a piezoelectric transducer for creating droplets from a liquid reservoir. In certain embodiments, the nebulizer is vibrating mesh nebulizer having perforated membranes actuated by an annular piezo element that vibrates in resonant bending mode.

[0054] In certain embodiments, administration is by intratracheal instillation, e.g., using a syringe. In certain embodiments, administration is by inhalation through a nostril or the mouth.

[0055] In certain embodiments, administration is daily or twice daily for more than one, two, three, four, five, or six weeks, or more than two months. In certain embodiments, administration is in combination with another active agent such as a bronchodilator, corticosteroid, antimuscarinic, antibiotic, nintedanib, pirfenidone, or combinations thereof.

[0056] In certain embodiments, the bronchodilator is a beta-2 agonist, such as salbutamol, salmeterol, formoterol and vilanterol or an anticholinergic, such as ipratropium, tiotropium, aclidinium, or glycopyrronium, or an antimuscarinic such as atropine or scopolamine, or theophylline.

[0057] In certain embodiments, administration is in combination with a bronchodilator such as albuterol, formoterol, or levalbuterol or salts thereof.

[0058] In certain embodiments, administration is in combination with a mucolytic agent such as bromhexine or salts thereof.

[0059] In certain embodiments, administration is in combination with a cystic fibrosis drug such as lumacaftor, elexacaftor, ivacaftor, tezacaftor, cavosonstat, olacaftor, posenacaftor, galicaftor, navocaftor, deutivacaftor, nesolicaftor, or combinations thereof.

[0060] In certain embodiments, administration is in combination with an anti-inflammatory agent such as a corticosteroid, fluticasone, or salts thereof.

[0061] In certain embodiments, administration is in combination with an antibiotic agent such as a macrolide, azithromycin, antipseudomonal, fluoroquinolones, ciprofloxacin, levofloxacin, ceftazidime, piperacillin and tazobactam, imipenem, aminoglycosides, aztreonam, tobramycin, colistin, colistimethate sodium, or salt thereof.

[0062] In certain embodiments, administration is in combination with other pharmaceutically active agents. These compounds include but are not limited to analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxiolytics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics, and antinarcoleptics.

[0063] Specific examples of the pharmaceutically active agents that can be adjunctively administered include, but are not limited to, aceclofenac, acetaminophen, atomoxetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, corticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptiline, desipramine, desomorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproex, dizatriptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamates, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketanserin, ketoprofen, ketorolac, lesopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol, mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methylsalycylate, metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, naratriptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprozin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pirlindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propranolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxetine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, tetrabenazine, thiazides, thioridazine, thiothixene, tiapride, taziprinone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone, and combinations thereof.

[0064] Examples Experiments performed in cancer cells indicate that GO-201 treatment results in growth arrest and cell death, while it has no effect on non-malignant mammary epithelial cells. In a mouse model of human tumor xenografts, administration of GO-201 was associated with loss of tumorigenicity and tumor necrosis which led to regression of tumor growth.

[0065] GO-201 was used to target MUC1 -dependent sustained EGFR activation leading to mucus EGFR-dependent MUC5AC expression, a major constituent of airway mucus in human lung epithelial cells (NCI-H292 cells) (Figure 1). Also contemplated is the use of GO-203 and GO-203- 2C which are second-generation derivatives of GO-201, e.g., truncated and contains all D-amino acids. GO-203-2C is the GO-203 peptide wherein the N-terminal is acylated, the C-terminal is an amide, and the thiol side chains of two cysteines for a disulfide bond. Cys in the ten position and the Cys in the twelve positions form a disulfide ring providing, acetyl-D-Arg-D-Arg-D-Arg-D- Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-[D-Cys-D-Gln-D-Cys]-D-Arg-D-Arg-D-Lys-D-Asn- NH2(Cys disulfide) (SEQ ID NO: 3)

Claims

CLAIMS1. A method of decreasing mucus hypersecretion in the lungs comprising administering an effective amount of the peptide selected from D-Arg-D-Arg- D-Arg-D-Arg-D-Arg-D-Arg-D-Arg- D-Arg-D-Arg-Cys-Gln-Cys-Arg-Arg-Lys-Asn-Tyr-Gly-Gln-Leu-Asp-Ue-Phe-Pro (SEQ ID NO: 1) (GO-201) or D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Cys-D-Gln- D-Cys-D-Arg-D-Arg-D-Lys-D-Asn (SEQ ID NO: 2) (GO-203), and acetyl-D-Arg-D-Arg-D-Arg- D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-D-Arg-[D-Cys-D-Gln-D-Cys]-D-Arg-D-Arg-D-Lys-D-Asn- NEb (SEQ ID NO: 3) (Cys disulfide) (GO-203-2C) to a subject in need thereof.

2. The method of claim 1, wherein the subject is diagnosed with chronic obstructive pulmonary disease (COPD).

3. The method of claim 1, wherein the subject is diagnosed with chronic rhinosinusitis.

4. The method of claim 1, wherein the subject is diagnosed with bronchiectasis.

5. The method of claim 1, wherein administration is by a nebulizer.

6. The method of claim 5, wherein the nebulizer is a jet nebulizer driven by compressed air.

7. The method of claim 5, wherein the nebulizer is an ultrasonic nebulizer having a piezoelectric transducer for creating droplets from a liquid reservoir.

8. The method of claim 5, wherein the nebulizer is vibrating mesh nebulizer having perforated membranes actuated by an annular piezo element to vibrate.

9. The method of claim 1, wherein administration is by a pressurized or unpressurized inhaler.

10. The method of claim 1, wherein administration is by a metered-dose inhaler.

11. The method of claim 1, wherein the subject is diagnosed with a bacterial infection.

12. The method of claim 1, wherein the peptide is administered in combination with a bronchodilator.

13. The method of claim 1, wherein the peptide is administered in combination with nintedanib.

14. The method of claim 1, wherein the peptide is administered in combination with pirfenidone.

15. The method of claim 1, wherein the peptide is administered in combination with an antiinflammatory agent.

16. The method of claim 1, wherein the peptide is administered in combination with an antibiotic agent.

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