Halogenated antibacterial peptoids

Abstract

formula and X, Y, and Z are independently selected from the group consisting of N-substituted glycine residues, wherein the N-substituents are independently selected from the group consisting of natural α-amino acid side chain moieties, isomers, and carbon homologs thereof, and at least one of A, B, X, Y, and Z comprises a halogen-containing moiety.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 841,227, filed April 30, 2019, which has the same name and has the same inventors, and which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to antimicrobial compositions, and more particularly to antimicrobial peptoids. [Background technology]

[0003] The use of natural antimicrobial peptides (AMPs) in the treatment of multidrug-resistant bacteria has been the focus of a considerable amount of research. AMPs are known to provide broad-spectrum protection against bacterial pathogens. These peptides have shown potential as supplements (or alternatives) to conventional antibiotics, as most bacteria have not evolved resistance to them. DISCLOSURE OF THE INVENTION [Problem to be solved by the invention]

[0004] AMPs destroy bacteria in a variety of ways. Some AMPs kill bacteria by penetrating the cytoplasmic membrane, causing depolarization and leakage of internal cellular material. Other AMPs function by targeting anionic bacterial components, such as DNA, RNA, or cell wall components. Bacterial resistance to AMPs is rare, likely because such AMPs have evolved with resistance mechanisms designed to evade the AMPs. When bacteria resist certain AMPs through the production of so-called "virulence factors," these virulence factors are molecules that bind to and inactivate certain human AMPs. However, in general, the targets of many AMPs (e.g., bacterial plasma membranes and anionic intracellular macromolecules) are sufficiently common that changes to the AMP sequence can be made to abolish resistance without significantly adversely affecting the overall functionality of the AMP.

[0005] Although AMPs have been actively studied for decades, only a few pareticular AMPs have achieved widespread clinical use (e.g., colistin, polymyxin E). This slow clinical adoption of AMPs is due in part to the vulnerability of many peptide therapeutics to rapid in vivo degradation (especially enzymatic and proteolytic degradation), which dramatically reduces their bioavailability. This necessitates large doses and significantly increases costs. [Means for solving the problem]

[0006] In one embodiment, the formula TIFF0007745323000001.tif10169, or a pharmaceutically acceptable salt thereof, is provided, A is a terminal N-alkyl-substituted glycine residue; n is an integer; B is selected from the group consisting of NH, one and two N-substituted glycine residues, wherein the one and two N-substituted glycine residues have N-substituents independently selected from natural α-amino acid side chain moieties, isomers and carbon homologs thereof; and X, Y, and Z are independently selected from the group consisting of N-substituted glycine residues, wherein the N-substituents are independently selected from the group consisting of natural α-amino acid side chain moieties, isomers and carbon homologs thereof, and proline residues, and at least one of A, B, X, Y, and Z comprises a halogen-containing moiety (or a bearing moiety).

[0007] In another aspect, the formula: TIFF0007745323000002.tif10169, or a pharmaceutically acceptable salt thereof, is provided, wherein B is selected from NH2 and X'; N RX, Y, Z, and X' are independently selected from N-substituted glycine residues comprising N-substituents, wherein the N-substituents of the N-substituted glycine residues are independently selected from naturally occurring α-amino acid side chain moieties, isomers and carbon homologs thereof, and proline residues, and at least one of the N-substituents comprises a halogen atom; n is an integer; and R is the N R N-alkyl substituents of glycine residues, said substituents being from about C4 to about C 20 is selected from linear, branched and cyclic alkyl moieties of the formula:

[0008] In a further embodiment, a poly-N-substituted glycine or a pharmaceutically acceptable salt thereof is provided with an N-terminal N-alkyl substituted glycine residue, wherein the alkyl substituent is from about C4 to about C 20 the C-terminus is selected from NH2, one and two N-substituted glycine residues, said N-substituents being α-amino acid side chain moieties and carbon homologs thereof; and from 2 to about 15 monomeric residues between said N- and C-termini; each said residue is independently selected from a proline residue and an N-substituted glycine residue, said N-substituents being independently selected from natural α-amino acid side chain moieties, isomers and carbon homologs thereof, and at least one said monomeric residue is N Lys wherein at least one of the N-substituents is chiral, the monomer residues are selected to provide the compound with a periodic or aperiodic sequence of monomer residues; and at least one of the residues contains at least one halogen substituent.

[0009] In yet another embodiment, there is provided a compound derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by replacing at least one hydrogen atom in at least one aryl moiety thereof with at least one halogen atom, or a pharmaceutically acceptable salt thereof.

[0010] In yet another embodiment, a method for treating or inhibiting a disease is provided, the method comprising administering to an individual having or at risk of developing the disease an amount of at least one poly-N-alkyl substituted glycine or a pharmaceutically acceptable salt thereof, wherein the amount of poly-N-alkyl substituted glycine is effective to treat or inhibit the disease, and the poly-N-alkyl substituted glycine compound has the formula TIFF0007745323000003.tif8169, wherein B is selected from NH2 and X'; N R X, Y, Z, and X' are independently selected from N-substituted glycine residues comprising N-substituents, wherein the N-substituents of the N-substituted glycine residues are independently selected from naturally occurring α-amino acid side chain moieties, isomers and carbon homologs thereof, and proline residues, and at least one of the N-substituents comprises a halogen atom; n is an integer; and R is the N R N-alkyl substituents of glycine residues, said substituents being from about C4 to about C 20 is selected from linear, branched and cyclic alkyl moieties of the formula:

[0011] In a further aspect, a method for treating or inhibiting a disease is provided, comprising administering to an individual having or at risk of developing said disease an amount of at least one poly-N-alkyl substituted glycine, or a pharmaceutically acceptable salt thereof, wherein said amount of poly-N-alkyl substituted glycine is effective to treat or inhibit said disease, and said poly-N-alkyl substituted glycine compound is a compound or a pharmaceutically acceptable salt thereof derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by replacing at least one hydrogen atom in at least one aryl moiety with at least one halogen atom.

[0012] In yet another aspect, there is provided a poly-N-substituted glycine compound containing at least one halogen selected from the group consisting of chlorine, bromine, and iodine, which preferably contains carboxamide end groups and is preferably prepared via rink amide resin. [Brief explanation of the drawings]

[0013] Figure 1 shows the molecular structures of first-generation peptoids containing halogen atoms. Different peptoid oligomeric structures are numbered 1-37 and 38-51.

[0014] Figure 2 is a set of graphs of small-angle X-ray scattering (SAXS) data showing scattering intensity plotted against the modulus of the scattering vector Q for 10-mer peptoids at 5 mg / ml and 37°C obtained at the BM29 beamline at the ESRF laboratory. Figure 2A shows the results for a fully halogenated peptoid, while Figure 2B shows the results for a semi-halogenated peptoid. A non-halogenated peptoid (compound 19) is included in both graphs as a reference. The results show primarily free, unstructured peptoid chains with a small fraction of sheet-like filaments for compounds 19-21 and 24-27, and defined bundles (seen as increased scattering intensity and a change in the shape of the curve) for compounds 22 and 23.

[0015] Figure 3 shows the complete SAXS results for fully iodinated peptoids (except for the 10-mer compound 23, which was measured at the ESRF) measured on a Bruker NANOSTAR instrumentation at the indicated concentrations along with model fits (fitted using the bundle model as described herein). Figures 3A, 3B, 3C, and 3D show the 6-mer (compound 5), 8-mer (compound 14), 10-mer (compound 23), and 12-mer (compound 32), respectively.

[0016] FIG. 4 shows chlorinated and brominated variants of peptoid 1 [H-(NLys-Nspe-Nspe)4-NH2], as well as truncated brominated peptoid 1 analogs.

[0017] FIG. 5 is a graph of IC50 curves of selected peptoids against the HaCaT cell line.

[0018] FIG. 6 shows the structure of peptoid 1 [H-(NLys-Nspe-Nspe)4-NH2], where NLys is N-(4-aminobutyl)glycine and Nspe is N-(S)-(1-phenylethyl)glycine.

[0019] 7-12 show the structures of some specific, non-limiting examples of halogenated analogs of peptoid 1.

[0020] FIG. 13 shows the structure of a shorter, modified version of peptoid 1, which contains 6 monomers instead of being composed of 12 monomers.

[0021] 14-16 show the structures of some specific, non-limiting examples of halogenated analogs of peptoids, the structures of which are shown in FIG.

[0022] FIG. 17 is a graph depicting the cytotoxicity (HaCaT cell line) of some of the peptoids disclosed herein.

[0023] Figure 18 shows the SAXS results for all decamers measured at the ESRF at the indicated concentrations, along with model fits (data for compounds 19-21 and 24-27 were fitted using a model for random polymer-like chains with a fiber-like cluster model (Eq. 1), while data for compounds 22 and 23 were fitted using a bundle model (Eq. 6)). DETAILED DESCRIPTION OF THE INVENTION

[0024] I. Background These problems have led to the development of peptidomimetics, small protein-like chains designed to mimic peptides. Peptidomimetics can be achieved by modifying existing peptides. Peptidomimetics can also be based on similar systems that mimic peptides (e.g., peptoids and β-peptides).

[0025] Peptoids (oligomers of N-substituted glycines) are isomers of peptides in which the side chain is attached to the backbone amide nitrogen rather than the α-carbon. Antibacterial peptoids are described, for example, in U.S. Patent No. 8,445,632 (Barron et al.), entitled "Selective Poly-N-Substituted Glycine Antibiotics," which is incorporated herein by reference in its entirety. Peptoids exhibit proteolytic stability and better bioavailability than corresponding peptides, while often retaining antibacterial activity.

[0026] Peptoids are particularly well suited for mimicking AMPs. They are easily synthesized using conventional peptide synthesizers, providing access to diverse sequences at relatively low cost. Submonomer synthesis methods are known that can be used to impart a wide variety of chemical functionality to peptoids. As a result, peptoids are highly tunable and precisely tunable. Furthermore, they are protease-resistant and can be engineered to form amphipathic helices that resist thermal and chaotropic denaturation.

[0027] Despite their promise, further improvements in peptoids are needed for these agents to achieve their full potential as antibacterial therapeutic agents. In particular, there is a need in the art for further improving the antibacterial efficacy of peptoids without a concomitant increase in cytotoxicity. Similarly, there is a need in the art for means to reduce the cytotoxicity of existing peptoids without a concomitant decrease in the antibacterial efficacy of these agents. There is also a need in the art for peptide mimetics with novel substituents that can increase the efficacy of existing peptoid agents against specific pathogens. Furthermore, there is a need in the art for means to manipulate the aggregate-forming ability of peptoids, which may contribute to the pharmaceutical efficacy of these agents.

[0028] The need for these improvements is underscored by the well-documented increasing resistance of many pathogens to current treatments. For example, in recent years, methicillin-resistant S. pseudintermedius (MRSP) strains have emerged worldwide. Methicillin-resistant S. pseudintermedius is resistant to all β-lactam antibiotics. Multidrug-resistant strains of this and other pathogens have also emerged, resistant to almost all currently available antibiotics. The most recent example is the novel strain of coronavirus that has led to the current COVID-19 pandemic.

[0029] Recently, it has been shown that the incorporation of fluorine atoms into certain peptidomimetics can improve the antibacterial activity of these compositions, while their hemolytic activity remains unaffected. See Molchanova N, Hansen PR, Damborg P, Franzyk H, "Fluorinated antimicrobial lysine-based peptidomimetics with activity against methicillin-resistant Staphylococcus pseudintermedius," J Pep Sci 2018;e3098 (Molchanova et al.). In particular, fluorination of certain peptidomimetics was found to have a significant effect on the activity of these materials against Gram-positive bacteria. However, the effects of introducing other halogens into antibacterial peptoids have not been extensively explored.

[0030] We have addressed this problem by synthesizing a library of halogenated peptoids. These peptoids contain one or more fluorine, chlorine, bromine, and / or iodine atoms and vary in length and level of halogen substitution at the 4-position of the phenyl ring. A clear correlation was observed between halogenation of an inactive model peptoid and its increased antibacterial activity.

[0031] As a result, chlorinated and brominated analogs of several known peptoids and their shorter counterparts have been produced. The shorter brominated analogs have shown significant improvements (up to 32-fold) in activity against Staphylococcus aureus, as well as significant improvements (16-64-fold) in activity against Escherichia coli and Pseudomonas aeruginosa. In many cases, these improvements in efficacy were achieved while also achieving reduced cytotoxicity.

[0032] Without wishing to be bound by theory, the biological effects of halogen substitution are thought to be related to the relative hydrophobicity and self-assembly properties of the resulting compounds. Small-angle X-ray scattering (SAXS) suggests that the self-assembled structure depends on (a) the size of the halogen, (b) the degree of substitution in the halogenated peptoid, and (c) the length of the peptoid. As described in more detail below, these characteristics correlate with the activity of these peptoids. II. Overview

[0033] The rapid emergence and widespread distribution of antibacterial resistance has been recognized as one of the most serious global threats to human health.[1-4] Most antibiotics in clinical use have become less effective in treating cases of infection caused by Gram-positive or Gram-negative superbugs.[5-6] As a result, there is a growing need in the art for novel antibiotics or alternative therapeutic agents that can be utilized to treat these pathogens.

[0034] Antimicrobial peptides (AMPs) are an essential part of the innate immune system of nearly all living organisms and remain a promising therapeutic strategy for combating bacterial infections.[7] AMPs have recently received increased attention due to the increasing antimicrobial resistance in many pathogens and the resulting need for new antibiotics. As a result, 36 different AMPs are currently undergoing clinical trials for a variety of infectious diseases.[8] However, the practical application of AMPs is limited by issues related to the rapid in vivo degradation and systemic toxicity of these substances. Currently, the production costs of these materials are also prohibitive.[9]

[0035] Poly-N-substituted glycines (peptoids) are a class of peptide mimetics in which the side chain is attached to the backbone amide nitrogen rather than the α-carbon.

[10] Antibacterial peptoids were first developed in 2003 (see Patch JA, Barron AE, "Helical peptoid mimics of magainin-2 amide," Journal of American Chemical Society 2003, 125: 12092-12093). Over the past 20 years, a variety of antibacterial peptoids have been produced. Many of these substances have been found to maintain their stability and antibacterial activity in vivo.

[11]

[0036] Over 4,000 halogenated compounds have been isolated from natural sources. This diverse group of natural products exhibits a wide range of biological activity, including anticancer and antibacterial properties.[12-13] However, until recently, limited attention has been paid to identifying the antibacterial properties of peptides and peptidomimetics containing halogen atoms. To date, fluorination has been of the greatest interest, but studies examining the relationship between fluorination and antibacterial activity have not yielded conclusive results.

[0037] For example, the introduction of hexafluoroleucine into magainins and buforins was found to confer enhanced antibacterial activity to these substances while retaining their low hemolytic properties. Similarly, the presence of a fluorine atom and a trifluoromethyl group was found to improve the potency of short cationic peptides.[14-16] In contrast, the incorporation of hexafluoroleucine into protegrin analogs resulted in a decrease in the potency of these analogs, while lipopeptide variants with fluorinated tails demonstrated only moderate antibacterial activity and significant hemolytic properties.[17-18]

[0038] Recently, Molchanova et al. reported an association between the introduction of fluorine atoms into peptidomimetic sequences and increased antibacterial activity of these substances against Gram-positive bacteria. This increase in antibacterial activity was achieved without adversely affecting hemolytic properties.[19-20] Similarly, both vancomycin and salinosporamide A have been found to require the presence of one or two chlorine substituents to achieve their antibacterial activity.[21-22]

[0039] Jia et al. found that the introduction of fluorine, chlorine, bromine, and iodine (via halogen-substituted phenylalanines) into the honey peptide Jelleine-1 led to improved protease stability. While one of the fluorinated analogs exhibited antibacterial activity similar to that of the parent peptide, the chlorinated, brominated, and iodinated analogs showed a 2- to 8-fold increase in activity in vitro.

[23] Interestingly, although the chlorinated and brominated versions showed greater potency in vivo, the iodinated analog had the greatest in vitro antibacterial activity.

[0040] Both chlorinated and brominated variants of the antibiotic NAI-107 showed greater antibacterial activity, with the brominated variant showing slightly greater potency.

[24]

[0041] The 12-mer peptoid 1 [H-(NLys-Nspe-Nspe)-NH] is a well-studied example of a promising antibacterial peptoid with broad-spectrum antibacterial activity, but exhibits a relatively high degree of cytotoxicity in vitro (note, however, that peptoid 1 has been tested and found to be reasonably well tolerated in vivo against Staphylococcus aureus intraperitoneally). See Czyzewski et al. (2016) In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents, PLoS ONE, 11(2): e0135961doi:10.1371 / journal.pone.0135961. PMCID: 26849681. Recent attempts to modify the structure of peptoid 1 to enhance its antibacterial activity have also been reported. However, it was found that the incorporation of fluorine or chlorine atoms into the Nspe unit of peptoid 1 did not result in a significant improvement in the antibacterial profile of this compound.

[25]

[0042] The introduction of halogens into the chemical structure of peptides or peptoids is generally known to increase the hydrophobicity of these molecules.

[26] This can lead to conformational changes and self-assembly into supramolecular nanostructures, driven by increased hydrophobic interactions. The correlation between antibacterial activity and self-assembly has been extensively discussed in the literature, where the impact on antibacterial properties and overall toxicity can be seen in both directions.[27-28] For example, Xu and coworkers found a link between increased antibacterial activity and the self-assembly of defined supramolecular nanofibers. On the other hand, Chu-Kung and coworkers found a clear tendency for fatty acid-linked peptides to exhibit reduced antibacterial activity.[29-30] Antibacterial peptoids have a significantly reduced tendency to fold and form secondary structures, and there appears to be no research directed at the effect of self-assembly on the antibacterial efficacy of peptoids.

[0043] A structure-activity study of halogenated peptoids is described below. The objectives of this study were to determine (a) the ability of halogenated peptoids to self-assemble into nanostructures and (b) the effect of the nature of the halogen and the amount of halogen substitution on the antibacterial activity of halogenated peptoids. The incorporation of halogen atoms into the scaffold of peptoid 1 and its repeating sequence elements was also investigated in an attempt to increase the antibacterial activity of this peptoid or modulate its cytotoxicity.

[0044] III. Results and Discussion A set of 36 peptoids was synthesized using scaffolds containing alternating NLys and Npm units, varying in length (6-, 8-, 10-, and 12-mer) and level of halogen substitution (full or alternating). Halogen atoms (fluorine, chlorine, bromine, or iodine) were introduced via the phenyl ring at the 4-position and synthesized using a submonomer method (see Figure 2).

[0045] All 36 peptoids were tested against seven bacterial strains: five Gram-positive strains (Staphylococcus aureus ATCC 25923 and ATCC 29213, methicillin-resistant Staphylococcus aureus USA 300, and methicillin-resistant Staphylococcus epidermidis ET-024 and ATCC 51625) and two Gram-negative strains (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa PA01) (see Table 1). Nonhalogenated peptoids showed no efficacy against the selected bacterial strains. Therefore, compounds 1, 10, 19, and 28 (6-mer, 8-mer, 10-mer, and 12-mer, respectively) represented inactive controls. Table 1: Minimum inhibitory concentrations (µg / mL) of first-generation peptoids containing halogen atoms TIFF0007745323000004.tif214169

[0046] The 36 compounds are divided into four sets according to their length: each set includes an unsubstituted control, four peptoids fully substituted with fluorine, chlorine, bromine, or iodine, and four "semi-substituted" peptoids (every other phenyl ring is substituted with a halogen atom).

[0047] Halogenation was found to have no effect on the activity of these peptoids against either Escherichia coli or Pseudomonas aeruginosa (see Table 1). However, across all sets, a clear correlation was observed between antibacterial activity against Gram-positive strains, the level of substitution, and the nature of the halogen. Fully halogenated peptoids demonstrated significantly enhanced activity against wild-type and resistant strains of Staphylococcus aureus and Staphylococcus epidermidis. Interestingly, activity in the hexamers (compounds 2–5) and octamers (compounds 11–14) increased from fluorine to iodine, with the latter being the most potent. The addition of just three iodine atoms to the 6-mers increased activity by more than 64-fold against S. aureus (MICs >512 μg / ml for 1 and 8 μg / ml for 5) and 256-fold against MRSE (MICs 512 μg / ml for 1 and 2 μg / ml for 5), while the 8-mer compound 14 showed similar activity against S. aureus and a 128-fold increase in activity against MRSE (MICs 256 μg / ml for 10 and 2 μg / ml for 14). However, as we progressed to the fully substituted 10-mer (compounds 20–23) and 12-mer (compounds 29–32) sets, the antibacterial trend was lost; in particular, compounds with iodine atoms showed lower potency against both S. aureus and multidrug-resistant S. epidermidis compared with their chlorinated and brominated analogs. Compared to the unsubstituted control peptoid, bromination of the 10-mer increased activity against S. aureus by more than 256-fold and 128-fold against S. aureus (S. aureus: MIC > 512 μg / mL for 19; 2 μg / mL for 22; MRSE: MIC 128 μg / mL for 19; 1 μg / mL for 22). In contrast, the brominated 12-mer analog showed similar or lower activity against both S. aureus and S. epidermidis.

[0048] The "half-substituted" set declined in a similar manner but generally showed similar or lower potency. Interestingly, the half-substituted peptoids bearing bromine exhibited activity comparable to their fully substituted analogs. For example, compound 26 exhibited MICs between 1 and 8 μg / mL, compared to 1 and 4 μg / mL for the fully substituted analog (compound 22).

[0049] As expected, the hydrophobicity of peptoids increased with the addition of halogen atoms; fluorine had a less pronounced effect, while the incorporation of iodine resulted in a significantly higher hydrophobicity profile. In parallel, the antibacterial activity of peptoids became a well-established correlation, where increased hydrophobicity led to increased antibacterial activity. However, once a certain hydrophobicity threshold was met (e.g., for compounds 23 and 32), activity was lost. This phenomenon has been observed previously in other peptide / peptoid studies. [31-32] Overall, the introduction of halogen atoms was found to result in increased hydrophobicity and increased antibacterial activity against Gram-positive bacteria. However, above a certain threshold of hydrophobicity, the activity of peptoids began to decrease.

[0050] VI. Materials / Methods The following materials and methodologies were utilized in the examples described herein. 1.General information

[0051] Starting materials and solvents were purchased from commercial suppliers (Iris Biotech, Sigma-Aldrich, and Merck) and used without further purification. Water used for analytical and preparative high-performance liquid chromatography (HPLC) was filtered through a 0.22 μm Millipore membrane filter.

[0052] For compounds 1–48, purity was determined by analytical HPLC using a Waters 717 plus Autosampler, In-line Degasser AF, 600 Controller, and 2996 Photodiode Array Detector; the column used was a Waters Symmetry C18, 5 μm, 4.6 mm × 250 mm. A gradient of aqueous acetonitrile (MeCN) with 0.1% trifluoroacetic acid (TFA) was employed (eluent A: 5:95 MeCN-HO + 0.1% TFA, eluent B: 95:5 MeCN-HO + 0.1% TFA). All tested compounds were at least 95% pure. Preparative HPLC was performed using a Waters XSelect Peptide CSH C18 OBD™, 5 μm, 19 mm × 250 mm column and the same eluents as the analytical HPLC. High resolution mass spectrometry (HRMS) spectra were obtained using a Waters QTOF Premier mass spectrometer equipped with an electrospray ionization source and a quadrupole and time-of-flight MS detector.

[0053] For compounds 49–51, pepl-6mer, and Peptoid 1, product purity was determined by analytical UPLC / MS using a Waters Acquity UPLC system equipped with an Acquity Diode Array UV detector and a Waters SQD2 mass spectrometer. A Waters Acquity UPLC Peptide BEH C18 column (300 Å pore size, 1.7 μm particle size, 2.1 mm × 100 mm) with an Acquity UPLC BEH C18 VanGuard pre-column (1.7 μm, 2.1 mm × 5 mm) was used as the stationary phase. Preparative HPLC purification was performed using a Waters Prepl50 LC system equipped with a Waters 2489 UV / Visible detector and a Waters Fraction Collector III collector. A Waters XBridge BEH300 Prep C18 column (5 μm particle size, 19 mm×10 mm) with a Waters XBridge Peptide BEH300 C18 VanGuard column (5 μm particle size, 19 mm×100 mm) was used as the stationary phase. 2. General Synthesis of Peptoids

[0054] All peptoids were synthesized manually on Rink Amide resin (Novabiochem, 0.65 mmol / g) using the submonomer method.

[10] After synthesis, the oligomers were cleaved and deprotected in trifluoroacetic acid (TFA) / triisopropylsilane / water (95:2.5:2.5 (v / v)) for 30 min. 3. Measurement of minimum inhibitory concentration

[0055] Bacterial growth inhibition was determined using broth microdilution by the Clinical Laboratory Standards Institute.

[37] The antibacterial activity of peptoids against biofilm-producing Staphylococcus aureus ATCC 25923, ATCC 29213, and methicillin-resistant Staphylococcus aureus USA 300, methicillin-resistant Staphylococcus epidermidis ATCC 51625, methicillin-resistant Staphylococcus epidermidis ET-02438, Pseudomonas aeruginosa Pa01 (H103), and Escherichia coli ATCC 25922 was investigated. Bacteria grown on agar plates for 18 hours at 37°C were diluted to ∼1 × 10 CFU / mL in Mueller-Hinton medium II (MHB II). Two-fold serial dilutions of peptoids in MHB II were inoculated with bacteria to achieve a final concentration of 5 × 10 CFU / mL in polypropylene 96 U-well microtiter plates (Corning™ 3897; ThermoFisher Scientific, Roskilde), followed by incubation for 18 h at 37°C in open air. MIC values ​​were determined as the lowest concentration showing no visible bacterial growth. Experiments were performed twice (technically in triplicate) on different days. 4.X-ray small angle scattering

[0056] SAXS experiments on the 10-mer peptoid were performed on the automated BM29 bioSAXS beamline at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France.

[39] Using an energy of 12.5 keV and a detector spacing of 2.87 m, data were acquired covering a q range of approximately 0.0047 Å-1 to 0.5 Å-1 (q = 4π sin(θ / 2) / λ, where θ is the scattering angle and λ is the X-ray wavelength). Data sets were calibrated to the absolute intensity scale using water as the primary standard. Samples (40 μL) were passed through the capillary using the flow mode of an automated sample changer.

[40] SAXS data were collected in 10 consecutive frames of 0.5 seconds each to monitor radiation damage, and data reduction was performed using standard tools at BM29.

[41]

[0057] SAXS experiments on the fully iodinated 6-, 8-, and 12-mers to determine the CAC of the compounds were performed using a Bruker NANOSTAR equipped with a microfocus X-ray source (Iμs Cu, Incoatec, Germany) and a VÅNTEC-2000 detector. Raw scattering data were calibrated to an absolute intensity scale using water as the primary standard and radially averaged to obtain 1D scattering intensity profiles as a function of the scattering vector with a wavelength of 1.54 Å. Two concentrations of compound 23 and compound 19 were also tested on the NANOSTAR to verify that the results were comparable to those from the synchrotron SAXS at the ESRF. 5.Cell culture

[0058] Immortalized human keratinocyte (HaCaT) cell line (a gift from David Gramnaim, Bispebjerg Hospital) was grown under standard conditions (5% CO2 / 95% O2 at 37°C) for 21–25 h and then cultured to ~90% confluence. Cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% (v / v) fetal bovine serum (FBS). All culture media were supplemented with penicillin (100 IU / mL) and streptomycin (100 μg / mL). All cell culture media and supplements were obtained from Sigma-Aldrich (St Louis, MO, United States). 96-well plates were obtained from Corning Costar (Sigma-Aldrich, Brondby, Denmark). 6. Cell viability measurement test

[0059] Cell viability was evaluated in cell monolayers grown to ~90% confluence in 96-well plates using the MTS / PMS assay as previously described.

[42] Briefly, adherent cells were washed with PBS solution (ThermoFisher Scientific, Roskilde) at 37 °C and exposed to 100 μL of peptide (at concentrations ranging from 0 to 1000 μg / mL) dissolved in the medium also used for culturing the cell line for 1 h at 37 °C. The cells were then washed twice with PBS at 37 °C. A 100 μL aliquot of the MTS / PMS solution in medium (consisting of 240 μg / mL MTS (Promega, Madison, WI, United States) and 2.4 mg / mL PMS (Promega, Madison, WI, United States)) was added to the cells, which were then incubated at 37 °C for 1 h while protected from light. Absorbance at 492 nm was measured using a plate reader (SpectraMax i3X; Molecular devices, San Jose, CA). Relative viability was calculated by using 0.2% (w / v) sodium dodecyl sulfate (SDS) as a positive control, while cells exposed to medium without the test compound were used as a negative control. Data were obtained in three independent biological replicates, which were performed on a total of six replicates on separate passages and separate days of the cells. 7. Theoretical modeling of data from SAXS a. Random polymer-like chains with fiber-like clusters

[0060] To extract accurate and detailed structural information, SAXS data for pure peptide chains were analyzed using the following Equation 1 with a combination of free chains and rectangular fibers characterized by dimensions a < b < c (where c is the fiber length and a and b are the X and Y directions of the cross-section): TIFF0007745323000005.tif16169 (Equation 1)

[43] . Here, φ is the volume fraction of the polymer, V p is the volume of the polymer, Δρ is the excess scattering length density, fchain is the fraction of free chains. N p (average number of peptides in each sheet) is N p =abc / V p It is defined as P chain (q) is the shape factor of the free peptoid chain given by the Debye equation for Gaussian chains: TIFF0007745323000006.tif16169 (Formula 2) where R g is the radius of rotation of the peptoid chain.

[0061] Assuming that the length of the peptoid sheets is much larger than their lateral dimensions (i.e., c >> a, b), the shape factor P sheet (q) is given by: TIFF0007745323000007.tif12169 (Formula 3) where the amplitude is given by TIFF0007745323000008.tif21169 (Formula 4) and TIFF0007745323000009.tif8169 (Formula 5) where: TIFF0007745323000010.tif10169b. Self-assembling peptides in solution: a peptide cylindrical bundle model

[0062] Each peptoid in the bundle is approximated as a simple solid cylinder given by: TIFF0007745323000011.tif26169 (Formula 6) where L is the total length of the cylinder, R is its radius, and α is the angle between the momentum transfer vector q and the cylinder axis parallel to L. J1 is a first-order Bessel function. The shape factor describing scattering for a bundle of parallel cylinders can be calculated using the formula given by Oster and Riley: TIFF0007745323000012.tif27169 (Formula 7) where J0 is the zeroth-order Bessel function and dij is the distance between the centers of the different cylinders. The above formula provides a general formula that can, in principle, be evaluated for any collection and number of cylinders. Here, we assume that a quadrilateral bundle of cylinders is utilized, with the bundle arranged in a square with the center of each cylinder at each corner. Thus, all inter-cylinder distances are d = 2fR, except for the diagonal distance, which is d = √8fR, where f is the expansion factor that adjusts the distance between the cylinders. Equation 7 is the shape factor, P(q) cyl can be rewritten in terms of the structure factor TIFF0007745323000013.tif9169 looks like this: TIFF0007745323000014.tif29169 (Formula 8)

[0063] The interactions between peptoid bundles seen at some of the highest concentrations can be modeled using expressions from the polymer reference interaction site model (PRISM) given by the structural factors

[44] : TIFF0007745323000015.tif13169 (Formula 9) where ν is a measure of the excluded volume and c(q) is the shape factor of an infinitely thin rod

[45] : TIFF0007745323000016.tif18169 (Formula 10) The total expression for intensity is given by: TIFF0007745323000017.tif18169 (Formula 11) where f agg is the fraction of peptoid chains assembled into bundles, and φ CAC =φ-(f agg *φ) to allow calculation of CAC. C. Peptoid nanostructure in solution SAXS results

[0064] Figure 18 shows the full SAXS results for all decamers measured at the ESRF at the indicated concentrations, along with the model fits (compounds 19-21 and 24-27 were fitted using random polymer-like chains with a fiber-like cluster model (Equation 1), while compounds 22 and 23 were fitted using a bundle model (Equation 6)). The full fit parameters are shown in Tables 2-3 below. Table 2: Full fit parameters for the decamer TIFF0007745323000018.tif175169 Table 3: Full fit parameters for fully iodinated peptoids with increasing length TIFF0007745323000019.tif58169 Example 1

[0065] This example demonstrates the effect of halogen substitution on peptoid self-assembly in solution.

[0066] To further understand the effect of varying the length, size, and degree of substitution of the halogen groups, the nanostructures of these compounds were studied in detail using small-angle X-ray scattering (SAXS). The results are depicted in Figure 3.

[0067] SAXS allows for the determination of whether these peptoids self-assemble into nanostructures or instead exist as single molecules in aqueous solution. [33-36] Furthermore, through detailed theoretical modeling, this technique allows for accurate estimation of molecular weight and shape, as well as the overall physical structure of the peptoid assemblies. Results reveal that the observed structures depend on the length and hydrophobicity of the various peptoids, and for some of them, self-assembly into defined nanostructures was observed. The scattering intensity is plotted as a function of the coefficient of the scattering vector, q = 4π sin(θ / 2) / λ, where λ is the wavelength of the X-rays and θ is the scattering angle (see Figure 3). Note that 1 / q has the dimension of length, and the quantity represents a kind of "measuring stick"; at low q, large structures are probed, while at high q, SAXS is more sensitive to localized structures.

[0068] For the 10-mers (compounds 19-27), the scattering curves for the fully brominated and fully iodinated peptoids (compounds 22 and 23, respectively) showed significantly higher intensities and different shapes compared to the remaining 10-mers (see Figures 3A and 3B). The latter showed a typical polymer-like scattering pattern for random (Gaussian) chains, while the rise at low q revealed smaller fractions of larger structures or aggregates. The rise at ~q indicated plate-like fibers. -2 follows a power law of ~q -4 There are no large aggregates that follow a power law. Fit analysis of these data using a model with a combination of free chains and rectangular fibers resulted in a radius of gyration (Rg) of the free chains of 7–9 Å and a small mole fraction of fiber-like sheets of only 0.001–0.0005% (see Supporting Information Table 2 for a complete list of fit parameters).

[0069] The scattering of the fully brominated and fully iodinated peptoids (compounds 22 and 23, respectively) did not show the same increase at low q, and therefore the overall shape at intermediate and high q could not be explained by the fit model described above. Instead, the scattering intensity showed a flat q dependence at low q, indicating discrete, smaller nanostructures. Data from both compounds can be analyzed using a bundle model in which cylinders representing folded / helical units assemble into trimeric / tetrameric bundles.

[34] Scattering over a concentration range of 5–0.6 mg / mL for both systems was analyzed simultaneously, and the resulting fit parameters are listed in Table 2. The fit analysis also revealed critical aggregation concentrations (CAC) for the self-assembled structures, showing CAC values ​​of 2.3 mg / mL and 0.5 mg / mL for the fully brominated and fully iodinated peptoids (compounds 22 and 23, respectively) (see Figure 17). The low CAC value of compound 23 may provide an explanation for the loss of antibacterial activity observed for the fully iodinated 10- and 12-mers (see Table 1), as more peptoid is "bound" to the bundle and less is available in the (presumably) active form as a monomer.

[0070] In the case of the fully brominated compound 22, the CAC was found to be higher than the MIC value, thus not affecting activity, as there is still a significant fraction of free peptoid chains that can interact with bacteria.

[0071] The CAC was found to be much lower for the fully iodinated compound 23, most likely due to a dramatic reduction in the availability of free monomeric peptoids, which explains the reduced antibacterial activity of this compound. As discussed in the introduction, a similar trend was observed by Chu-Kung A. and coworkers. They concluded that a CAC close to the MIC of the free chain in their peptide system resulted in a lack of antibacterial activity in the same way as we observed for compound 23.

[29] Example 2

[0072] This example demonstrates the effect of hydrophobicity on the self-assembly properties of peptoids.

[0073] To further determine whether the low CAC value resulting from the 10-mer (compound 23) provides an explanation for the observed MIC data, the 6-, 8-, and 12-mer forms of fully iodinated peptoids (compounds 5, 14, 23, and 32, respectively) were examined. The results are shown in Figure 3 (see Table 3 for fit parameters). From the fit analysis, a CAC of 2.8 mg / ml was observed for the fully iodinated 6-mer compound 5, whereas a CAC of 1.4 mg / ml was observed for the 8-mer compound 14 and a CAC of 0.4 mg / ml was observed for the 12-mer compound 32.

[0074] These results indicate that even at very short lengths, these peptoids self-assemble due to their high hydrophobicity, as evidenced by the retention times in Table 1. However, the detected CACs are still highly correlated with peptoid length. In particular, the CACs of hexamers and octamers were lower than the MIC values ​​for these compounds; therefore, a clear correlation between CAC and MIC could not be established. This contrasts with the fatty acid-binding peptides studied by Chu-Kung A. and coworkers, who found such a correlation.

[29] Thus, the decreased activity observed for the 10- and 12-mers appears to be related to their increased hydrophobicity, indicating a threshold that remains rather than the self-assembly property itself. However, further study of the consequences of hydrophobicity and self-assembly on peptoid activity and toxicity is needed to fully explain the observed trends. Example 3

[0075] This example demonstrates the effect of halogenation on the antibacterial efficacy of peptoids.

[0076] To investigate whether halogen substitution can be used as a tool to improve the antibacterial potency of known peptoids, we synthesized two small libraries of chlorinated and brominated analogs of a well-studied peptoid (peptoid 1). (These halogenated analogs showed overall higher potency compared to the fluorinated analogs, while the iodinated analogs raised concerns about aggregation and loss of activity.) Both halogen atoms were introduced via Nspe units at the 4-position on the phenyl ring. The level of substitution varied between full substitution (all phenyl rings have halogen atoms) and "half" substitution (every other phenyl ring has a halogen atom). This strategy resulted in six chloro- and six bromo-modified versions of peptoid 1, depicted in Figure 4.

[0077] A library of 12 compounds (compounds 37–48) was tested against the same panel of bacterial strains as the first generation of peptoids. However, none of the modifications resulted in increased potency, while most caused a loss of activity (see Table 4 below). Judging from the long, elevated HPLC retention times, this may be explained by the fact that a critical hydrophobicity level was reached, which caused aggregation and loss of activity similar to that observed for compounds 23 and 32 (notably, the highest activity was observed for compounds with lower retention times). Interestingly, although compounds 38 and 40–42 have the same number of chlorine atoms, their hydrophobicity differs slightly. For the brominated derivatives (compounds 44 and 46–48), this effect was even more pronounced. This indicates that uniform distribution of halogen atoms across the peptoid chain results in higher hydrophobicity compared to allocating chlorine or bromine atoms at the termini or center of the peptoid sequence. Table 4: MICs (μg / mL) of chlorinated and brominated analogs of peptoid 1 TIFF0007745323000020.tif102169 Example 3

[0078] This example demonstrates the effect of halogenation on the antibacterial activity of an inactive short-chain analog of peptoid 1 (Pep1-hexamer).

[0079] As can be seen from the increased retention time, hydrophobicity plateaued upon introduction of halogen into the sequence of the peptoid, peptoid 1 (see Table 4). Therefore, the effect of shortening the length of peptoid 1 from 12 to 6 residues (cutting its length in half) was investigated. To this end, a small library of four analogs was synthesized with different halogenation levels (see Figure 4). As can be seen from Tables 3 and 4, the introduction of fluorine did not result in the desired increase in activity, whereas bromination had a more pronounced effect on hydrophobicity than chlorination, similar to that exhibited by iodine-containing peptoids. Therefore, three brominated short peptoid analogs of peptoid 1 (compounds 49–51) and one non-halogenated peptoid, Pep1-hexamer, were synthesized and tested against the same bacterial strains as the previous peptoid. The resulting data are shown below in Table 5, where the new data set is compared to the original peptoid (peptoid 1) data. Table 5: MIC (μg / mL) and IC50 (μg / mL) of short brominated peptoid Peptoid 1 analogs against HaCaT cell line TIFF0007745323000021.tif75169

[0080] Compound 49 has only one terminal bromine, while compound 50 has two bromine atoms. In compound 51, all four phenyl rings are substituted with bromine atoms. The addition of only two bromine atoms was sufficient to improve the activity of the inactive short analog, Pep1-hexamer, by 16- to 32-fold against both Staphylococcus aureus and Staphylococcus epidermidis. Incorporation of two additional bromine substituents (bringing the total to four) did not significantly affect activity. On the other hand, the addition of a single terminal halogen atom was already sufficient to confer several-fold increases in antibacterial activity. In contrast to previous data (in which the introduction of a halogen did not improve activity against Gram-negative bacteria), in this case the addition of two bromine atoms provided sufficient hydrophobicity to obtain MICs against Pseudomonas aeruginosa close to that of the parent peptoid (Peptoid 1), and a 32-fold increase in activity against Escherichia coli compared to Pep1-hexamer was achieved.

[0081] Since the incorporation of halogens was found to improve the activity of inactive peptoids, the cytotoxicity profiles of the resulting compounds were examined. Peptoid 1, Pep1-hexamer, and three brominated analogs were tested against the HaCaT cell line for 1 hour. Results were obtained using the MTS / PMS assay (see Figure 5, Table 3).

[0082] A clear trend was observed between the number of halogen atoms and the corresponding increase in cytotoxicity. However, although compound 50 exhibited the same antibacterial activity profile as peptoid 1, it was less cytotoxic, with an IC50 of 146.9 μg / mL compared to only 35.0 μg / mL for the latter. Although compounds 50 and 51 exhibited similar activity and hydrophobicity profiles, initial results indicate reduced cytotoxicity of the brominated analogs when compared to peptoid 1. V. Conclusion

[0083] The preceding examples demonstrate the effect of fluorine, chlorine, bromine, and iodine substitution on the antibacterial activity of peptoids. First, the inactive form (NLys-Npm) n Using a peptoid scaffold, it was shown that the incorporation of chlorine or bromine could provide improved antibacterial activity against Gram-positive bacteria, although fluorination did not have any significant effect. Introduction of iodine into the 6- and 8-mer analogs dramatically increased activity, but resulted in a loss of activity due to aggregation in the 10- and 12-mers. Attempts to improve the antibacterial potency of peptoid 1 by incorporating chlorine or bromine atoms through the Nspe unit resulted in an overall loss of activity. Without wishing to be bound by theory, this suggests that the hydrophobic limit had been reached. However, bromination of a shorter, inactive 6-mer analog of peptoid 1 resulted in the same activity as the 12-mer peptoid 1 against several bacteria, while at the same time significantly improving its cytotoxicity profile.

[0084] The foregoing demonstrates that halogenation (and especially bromination) can be used to easily modify and alter the physicochemical and antibacterial properties of peptoids, but the effect is highly dependent on the choice of halogen. Furthermore, this effect is sequence- and length-specific, and the inclusion of a halogen can also reduce antibacterial activity. VI. Other

[0085] The compositions described herein can be halogenated in a variety of ways. For example, these compounds can contain any number of halogen substitutions with the same or different halogens. In particular, these compounds can contain one or more fluoro-, chloro-, bromo-, or iodo-substitutions, and can contain substitutions with two or more distinct halogens. However, in many applications, the use of one or two bromo- or chloro-substitutions is preferred. Furthermore, the peptoids described herein can be halogenated at various positions; para-halogenation on the peptoid-containing aryl ring is particularly preferred in many applications, although ortho- and meta-substitutions, or even perhalogenation, may be useful in some applications.

[0086] The halogenated compositions described herein can also be alkylated, preferably with terminal alkylation, with alkylation (and especially terminal alkylation) via the C10 or C13 tail being particularly preferred. It has been found that such terminal alkylation can dramatically enhance the antibacterial activity of peptoids, and in some cases can confer significant antibacterial activity to peptoids that otherwise have low antibacterial activity.

[0087] The use of poly-N-substituted glycine compounds in the compositions and methodologies described herein is preferred. Preferably, these poly-N-substituted glycine compounds are poly-N-substituted glycines having the formula: TIFF0007745323000022.tif8169In formula, A is a terminal N-alkyl substituted glycine residue, n is an integer, B is selected from the group consisting of NH, one and two N-substituted glycine residues, said one and two N-substituted glycine residues having N-substituents independently selected from naturally occurring α-amino acid side chain moieties, isomers and carbon homologs thereof; X, Y, and Z are independently selected from the group consisting of N-substituted glycine residues, wherein the N-substituents are independently selected from the group consisting of natural α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of A, B, X, Y, and Z contains a halogen-containing moiety. The alkyl substituents are preferably from about C4 to about C6. 20 wherein n preferably has a value in the range of 1 to 3. Preferably, at least one of the X, Y and Z residues is N Lys and at least one of the N-substituents is chiral. Preferably, at least one of Y and Z is a proline residue. More preferably, A is a terminal N-alkyl-substituted glycine residue, wherein the alkyl substituent is from C6 to about C 18 wherein B is NH and n is 1 or 2. In some embodiments, A is a terminal N-alkyl substituted glycine residue, wherein the alkyl substituent is from about C to about C 18 wherein B is selected from the group consisting of N Lys residue, and where n is 1. In some embodiments, the compound may be a hexamer or a dodecamer.

[0088] In the aforementioned poly-N-substituted glycines, the halogen-containing moiety may be, for example, a halogen-substituted aryl moiety, such as a chloro-substituted aryl moiety, a bromo-substituted aryl moiety, or an iodo-substituted aryl moiety. In certain embodiments, each mer may contain a halogen-substituted aryl moiety, while in other embodiments, some of the mers may contain a halogen-substituted aryl moiety, and some of the mers in a hexamer may contain a halogen-free aryl moiety. In still other embodiments, exactly one mer contains a halogen-substituted aryl moiety. In some embodiments of the aforementioned poly-N-substituted glycines, at least two of A, B, X, Y, and Z contain a halogen-containing moiety, while in other embodiments, all of A, B, X, Y, and Z contain a halogen-containing moiety. While the aforementioned poly-N-substituted glycines may contain halogen substitution, including any halogen, substitution with chlorine, bromine, and / or iodine is preferred, with parahalogenation of the aryl moiety on these poly-N-substituted glycines being particularly preferred.

[0089] In some embodiments, the poly-N-substituted glycine may be a compound derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by substituting at least one hydrogen atom in at least one aryl moiety thereof with at least one halogen atom, and more preferably by substituting at least one para-hydrogen atom in at least one aryl moiety thereof with at least one halogen atom. In some embodiments, the compound is derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by substituting one hydrogen atom in each aryl moiety thereof with at least one halogen atom. In the foregoing embodiments, the at least one halogen atom is preferably selected from the group consisting of chlorine, bromine, and iodine. In some embodiments, the at least one halogen atom may include at least a first and a second distinct halogen selected from the group consisting of chlorine, bromine, and iodine. Particularly preferred embodiments of these poly-N-substituted glycines include the following compounds (or pharmaceutically acceptable salts thereof): TIFF0007745323000023.tif141153

[0090] Some embodiments of the compositions and methods disclosed herein may utilize poly-N-substituted glycine compounds containing at least one halogen selected from the group consisting of chlorine, bromine, and iodine. The poly-N-substituted glycine compounds contain at least one halogen selected from the group consisting of chlorine, bromine, and iodine, preferably at least two halogens, and in some cases at least four halogens. For example, the poly-N-substituted glycine compounds may contain at least two bromine atoms or at least two chlorine atoms, or may contain at least four bromine atoms or at least four chlorine atoms. Preferably, the poly-N-substituted glycine compounds contain at least one parahalogenated aryl group, more preferably at least two parahalogenated aryl groups, and in some cases at least four parahalogenated aryl groups. In particularly preferred embodiments, the poly-N-substituted glycine compounds contain carboxamide end groups. Such compounds can be prepared via rink amide resin.

[0091] The peptoids described herein can be incorporated into a variety of pharmaceutical compositions that can be used for a variety of purposes, including antibacterial, antifungal, and possibly antiviral and antiparasitic compositions. The pharmaceutical compositions utilized in the systems and methods disclosed herein can utilize one or more active ingredients that can be dissolved, suspended, or disposed of in a variety of media. Such media can include, for example, various liquid, solid, or multi-state media, such as emulsions, gels, or creams. Such media can include liquid media that may be hydrophobic or may contain one or more triglycerides or oils. Such media can include, but are not limited to, vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures thereof.The triglycerides used in these pharmaceutical compositions include: almond oil; babassu oil; borage oil; blackcurrant seed oil; black seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; peanut oil; mustard oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; glyceryl tricaprylate; glyceryl tricaprate; glyceryl tricaprate; glyceryl triandecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl caprylate / caprate; glyceryl tricaprylate / caprate / laurate; glyceryl tricaprylate / caprate / linoleate; glyceryl tricaprylate / caprate / stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic / capric glycerides; modified triglycerides; fractionated triglycerides; and mixtures thereof. The invention may include those selected from the group consisting of: The use of coconut oil is particularly preferred.

[0092] Various fatty acids can be used in the pharmaceutical compositions disclosed herein.These include, but are not limited to, both long-chain and short-chain fatty acids.Examples of such fatty acids include, but are not limited to, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, butyric acid, and pharmaceutically acceptable salts thereof.

[0093] The pharmaceutical compositions disclosed herein can be applied in various ways. Thus, for example, these compositions can be applied orally, transdermally, transmucosally, intravenously or by injection, or via a cell-based drug delivery system. Furthermore, these compositions can be applied in a single dose, multiple doses, or in a controlled release manner.

[0094] The pharmaceutical compositions disclosed herein can be prepared as tablets, liquids, gels, foams, ointments, or powders. In some embodiments, these compositions may be applied as microparticles or nanoparticles, via aerosols or sprays, or as dispersed micelles (which are totally water soluble) containing self-assembled peptoids within the micelles.

[0095] A variety of counterions can be utilized to form pharmaceutically acceptable salts of the materials disclosed herein. Those skilled in the art will understand that the specific choice of counterion can be determined by various considerations. However, in some applications, the use of sodium salts and hydrochloride salts may be preferred. Generally, the self-assembling peptoid is first dissolved in the absence of divalent counterions such as manganese, magnesium, calcium, etc.

[0096] In certain embodiments, the compositions described herein may be formulated as mixtures of different peptoid compounds. For example, in some embodiments, mixtures of two or more halogenated peptoids of the type disclosed herein may be formed. In other embodiments, mixtures of one or more halogenated peptoids described herein may be formed with one or more non-halogenated peptoids, including, for example, the peptoids described in U.S. Pat. No. 8,445,632 (Barron et al.), entitled "Selective Poly-N-Substituted Glycine Antibiotics," which is incorporated herein by reference in its entirety. It should also be noted that halogenated analogs of any of the peptoids disclosed in the '632 patent may be prepared according to the teachings herein.

[0097] A variety of cyclic peptoids can be produced in accordance with the teachings herein. These include, but are not limited to, halogenated analogs of the cyclic peptoids disclosed in U.S. Patent No. 9,938,321 (Kirshenbaum et al.), U.S. Patent No. 9,315,548 (Kirshenbaum et al.), and U.S. Patent No. 8,828,413 (Kirshenbaum et al.), all of which are incorporated herein by reference in their entireties. These halogen analogs can be characterized by halogen substitution with one or more halogens on one or more ring structures, but preferably include bromo- or chloro-substituted analogs.

[0098] The compositions and methodologies disclosed herein can be used to treat a variety of diseases caused by a variety of pathogens. These treatments can utilize a variety of other pharmaceutically active or effective substances, such as, for example, pulmonary surfactants, collectins, peptides, peptoids, peptidomimetics, aminoglycoside antibiotics, or vaccines. Pathogens treatable with these therapies can include viruses (including, but not limited to, SARS-CoV-2), bacteria (including gram-positive and gram-negative bacteria), fungi, and parasites.

[0099] A variety of terms of diseases can be treated with the compositions and methodologies disclosed herein. Examples of such diseases of the fungal taxonomy include, but are not limited to, aspergillosis, candidiasis, mucormycosis, histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis. Examples of such bacteriological diseases include, but are not limited to, brucellosis, campylobacter infections, cat scratch disease, chlamydia infections, cholera, Escherichia coli infections, gonorrhea, Klebsiella, Enterobacter, and Serratia infections, Legionella infections, meningococcal infections, whooping cough, plague, Mycobacterium tuberculosis infections, pseudomonas infections, salmonellosis, shigellosis, typhoid fever, and tularemia, splenic ulcers, diphtheria, enterococcal infections, erysipelotrichosis, listeriosis, nocardiosis, pneumococcal infections, staphylococcal infections, streptococcal infections, spirochetal infections such as Borrelia burgdorferi, bejel, yaws, and pinta, leptospirosis, Lyme disease, rat-bite fever, relapsing fever, syphilis, actinomycosis, bacteroides, botulism, clostridial infections, and tetanus. Examples of such diseases of viral origin include, for example, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease (COVID-19); enterovirus infections, bornavirus infections; herpesvirus infections; cytomegalovirus, e.g., HHV6A and HHV7, hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus, human papillomavirus (HPV); influenza; Japanese encephalitis; measles, mumps, and rubella; polio; rabies; rotavirus; chickenpox; shingles; and yellow fever, and infections caused by enveloped RNA viruses, including HIV-1 (e.g., including those caused by alphacoronaviruses and betacoronaviruses, specifically, but not limited to, SARS-CoV-2). Parasitic infections include those involving Toxoplasma gondii and Trypanosoma cruzi.

[0100] The above description of the present invention is illustrative and not intended to be limiting. Accordingly, it is apparent that various additions, substitutions, and modifications may be made to the above-described embodiments without departing from the scope of the present invention. Accordingly, the scope of the present invention should be interpreted with reference to the appended claims. For convenience, some features of the claimed invention may be set out separately in certain dependent or independent claims. However, it will be appreciated that these features may be combined in various combinations and subcombinations without departing from the scope of the present disclosure. By way of example, and not limitation, the limitations of two or more dependent claims may be combined with each other without departing from the scope of the present disclosure. The following is the invention as originally described in the present application. <Claim 1> formula TIFF0007745323000024.tif8169, or a pharmaceutically acceptable salt thereof, wherein A is a terminal N-alkyl substituted glycine residue, n is an integer, B is selected from the group consisting of NH, one and two N-substituted glycine residues, said one and two N-substituted glycine residues having N-substituents independently selected from natural α-amino acid side chain moieties, isomers and carbon homologs thereof; A poly-N-substituted glycine compound or a pharmaceutically acceptable salt thereof, wherein X, Y, and Z are independently selected from the group consisting of N-substituted glycine residues, wherein the N-substituents are independently selected from the group consisting of natural α-amino acid side chain moieties, isomers and carbon homologs thereof, and proline residues, and at least one of A, B, X, Y, and Z comprises a halogen-containing moiety. <Claim 2> The alkyl substituent is from about C4 to about C 20 2. The compound of claim 1, wherein the alkyl moiety is selected from the group consisting of linear, branched, and cyclic alkyl moieties. <Claim 3> 2. The compound of claim 1, wherein n has a value in the range of 1 to 3. <Claim 4> At least one of the X, Y and Z residues is N Lys and at least one of the N-substituents is chiral. <Claim 5> 2. The compound of claim 1, wherein at least one of Y and Z is a proline residue. <Claim 6> 2. The compound of claim 1, wherein Y and Z are proline residues. <Claim 7> A is a terminal N-alkyl substituted glycine residue, and the alkyl substituent is C6 to about C 18 wherein B is NH2 and n is 1 or 2. <Claim 8> A is a terminal N-alkyl substituted glycine residue, and the alkyl substituent is from about C to about C 18 and B is selected from the group consisting of N Lys The compound of claim 1, wherein n is a residue and n is 1. <Claim 9> 2. The compound of claim 1, wherein the compound is a hexamer. <Claim 10> The compound of claim 1, wherein the compound is a 12-mer. <Claim 11> The compound of claims 1-10, wherein the halogen-containing moiety comprises a halogen-substituted aryl moiety. <Claim 12> The compound of claims 1-10, wherein the halogen-containing moiety comprises a chloro-substituted aryl moiety. <Claim 13> The compound of claims 1-10, wherein the halogen-containing moiety comprises a bromo-substituted aryl moiety. <Claim 14> The compound of claims 1-10, wherein the halogen-containing moiety comprises an iodo-substituted aryl moiety. <Claim 15> 10. The compound of claim 9, wherein each mer in the hexamer contains a halogen-substituted aryl moiety. <Claim 16> 10. The compound of claim 9, wherein some of the mers in the hexamer contain halogen-substituted aryl moieties and some of the mers in the hexamer contain halogen-free aryl moieties. <Claim 17> 10. The compound of claim 9, wherein exactly one of the mers in the hexamer contains a halogen-substituted aryl moiety. <Claim 18> 11. The compound of claim 10, wherein each mer in the hexamer contains a halogen-substituted aryl moiety. <Claim 19> 11. The compound of claim 10, wherein some of the mers in the hexamer contain halogen-substituted aryl moieties and some of the mers in the hexamer contain halogen-free aryl moieties. <Claim 20> 11. The compound of claim 10, wherein only the first and last mers in the hexamer contain a halogen-substituted aryl moiety. <Claim 21> 10. The compound of claim 1, wherein at least two of A, B, X, Y, and Z contain a halogen-containing moiety. <Claim 22> 10. The compound of claim 1, wherein A, B, X, Y, and Z all contain halogen-containing moieties. <Claim 23> 10. The compound of claim 1, wherein the compound is an antibacterial compound. <Claim 24> A pharmaceutically acceptable salt of the compound according to claims 1 to 23. <Claim 25> formula TIFF0007745323000025.tif8169, or a pharmaceutically acceptable salt thereof, wherein: B is selected from NH2 and X'; N RX, Y, Z, and X' are independently selected from N-substituted glycine residues comprising N-substituents, wherein the N-substituents of the N-substituted glycine residues are independently selected from naturally occurring α-amino acid side chain moieties, isomers and carbon homologs thereof, and proline residues, and at least one of the N-substituents comprises a halogen atom; n is an integer; and R is the N R N-alkyl substituents of glycine residues, said substituents being from about C4 to about C 20 or a pharmaceutically acceptable salt thereof. <Claim 26> 26. The compound of claim 25, wherein n is 2 and B is NH2. <Claim 27> 26. The compound of claim 25, wherein n is 1 and B is X'. <Claim 28> At least one of X and X' is N Lys 28. The compound of claim 27, which is a residue. <Claim 29> The N-alkyl substituent is from about C to about C 18 29. The compound of claim 28, wherein the alkyl moiety is selected from the group consisting of linear, branched, and cyclic alkyl moieties of the formula: <Claim 30> X and X' are N Lys 30. The compound of claim 29, which is a residue. <Claim 31> formula The compound described in claim 30 of TIFF0007745323000026.tif9169. <Claim 32> The alkyl substituent is from about C4 to about C 20 26. The compound of claim 25, wherein the alkyl moiety is selected from the group consisting of linear, branched, and cyclic alkyl moieties of the formula: <Claim 33> 26. The compound of claim 25, wherein n has a value in the range of 1 to 2. <Claim 34> At least one of the X, Y and Z residues is N Lysand at least one of the N-substituents is chiral. <Claim 35> 26. The compound of claim 25, wherein at least one of Y and Z is a proline residue. <Claim 36> 26. The compound of claim 25, wherein Y and Z are proline residues. <Claim 37> A is a terminal N-alkyl substituted glycine residue, said alkyl substituent being from C6 to about C 18 and n is 1 or 2. <Claim 38> N R is a terminal N-alkyl substituted glycine residue, and the alkyl substituent is from about C to about C 18 and B is selected from the group consisting of N Lys 26. The compound of claim 25, wherein n is a residue and n is 1. <Claim 39> 26. The compound of claim 25, wherein the compound is a hexamer. <Claim 40> 26. The compound of claim 25, wherein the compound is a 12-mer. <Claim 41> 41. The compound of claims 25-40, wherein the halogen-containing moiety comprises a halogen-substituted aryl moiety. <Claim 42> 41. The compound of claims 25-40, wherein the halogen-containing moiety comprises a chloro-substituted aryl moiety. <Claim 43> 41. The compound of claims 25-40, wherein the halogen-containing moiety comprises a bromo-substituted aryl moiety. <Claim 44> 41. The compound of claims 25-40, wherein the halogen-containing moiety comprises an iodo-substituted aryl moiety. <Claim 45> 40. The compound of claim 39, wherein each mer in the hexamer contains a halogen-substituted aryl moiety. <Claim 46> 40. The compound of claim 39, wherein some of the mers in the hexamer contain halogen-substituted aryl moieties and some of the mers in the hexamer contain non-halogen-containing aryl moieties. <Claim 47> 40. The compound of claim 39, wherein exactly one of the mers in the hexamer contains a halogen-substituted aryl moiety. <Claim 48> 41. The compound of claim 40, wherein each mer in the hexamer contains a halogen-substituted aryl moiety. <Claim 49> 41. The compound of claim 40, wherein some of the mers in the hexamer contain halogen-substituted aryl moieties and some of the mers in the hexamer contain non-halogen-containing aryl moieties. <Claim 50> 41. The compound of claim 40, wherein only the first and last mers in the hexamer contain a halogen-substituted aryl moiety. <Claim 51> N R 26. The compound of claim 25, wherein at least two of X, Y, Z and X' contain a halogen-containing moiety. <Claim 52> N R 26. The compound of claim 25, wherein X, Y, Z and X' all contain a halogen-containing moiety. <Claim 53> 26. The compound of claim 25, wherein the compound is an antibacterial compound. <Claim 54> A pharmaceutically acceptable salt of the compound according to any one of claims 25 to 53. <Claim 55> A poly-N-substituted glycine compound or a pharmaceutically acceptable salt thereof, said compound comprising an N-terminal N-alkyl substituted glycine residue, said alkyl substituent being from about C4 to about C 20the C-terminus is selected from NH2, one and two N-substituted glycine residues, said N-substituents being independently selected from α-amino acid side chain moieties and carbon homologs thereof; and each of the 2 to about 15 monomeric residues between said N-terminus and C-terminus is independently selected from proline residues and N-substituted glycine residues, said N-substituents being independently selected from natural α-amino acid side chain moieties, isomers thereof and carbon homologs thereof, and at least one of said monomeric residues is N Lys wherein at least one of the N-substituents is chiral and the monomer residues are selected to provide the compound with a non-periodic sequence of monomer residues; and at least one of the residues contains at least one halogen, or a pharmaceutically acceptable salt thereof. <Claim 56> The N-terminus is an N-alkyl substituted glycine residue, and the alkyl substituent is from about C6 to about C 18 56. The compound of claim 55, wherein the linear alkyl moiety is selected from: <Claim 57> 57. The compound of claim 56, wherein the monomer residues comprise 2 to 5 (XYZ) acyclic trimers. <Claim 58> 58. The compound of claim 57, wherein at least one X, Y and Z in each of said trimers is selected to interrupt 3-fold periodicity. <Claim 59> 58. The compound of claim 57, wherein the monomer residue comprises at least two non-contiguous repeating trimers with at least one residue therebetween. <Claim 60> At least one X in at least one of said trimers is N Lys residue, and at least one of Y and Z in at least one said trimer is a proline residue. <Claim 61> 56. The compound of claim 55, wherein the at least one halogen is selected from the group consisting of bromine, chlorine, and iodine. <Claim 62> 56. The compound of claim 55, wherein at least one of the residues comprises at least one halogen-substituted aryl moiety. <Claim 63> 56. The compound of claim 55, wherein each of said residues comprises at least one halogen-substituted aryl moiety. <Claim 64> 56. The compound of claim 55, wherein some of the residues comprise at least one halogen-substituted aryl moiety and some of the residues comprise at least one non-halogenated substituted aryl moiety. <Claim 65> 65. The compound of claims 62-64, wherein the halogen-substituted aryl moiety is para-substituted. <Claim 66> 65. The compound of claims 62-64, wherein the halogen-substituted aryl moiety is perhalogenated. <Claim 67> A pharmaceutically acceptable salt of the compound according to any one of claims 55 to 66. <Claim 68> A compound derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by replacing at least one hydrogen atom in at least one aryl moiety thereof with at least one halogen atom. <Claim 69> 69. The compound of claim 68, derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by replacing at least one para-hydrogen atom in at least one aryl moiety thereof with at least one halogen atom. <Claim 70> 69. The compound of claim 68, derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by replacing one hydrogen atom in each aryl moiety thereof with at least one halogen atom. <Claim 71> 71. The compound according to claim 68, wherein the at least one halogen atom is selected from the group consisting of chlorine, bromine, and iodine. <Claim 72> 71. The compound of claims 68-70, wherein the at least one halogen atom comprises at least a first and a second distinct halogen selected from the group consisting of chlorine, bromine, and iodine. <Claim 73> The compound TIFF0007745323000027.tif47169. 69. The compound of claim 68, wherein: <Claim 74> The compound The compound of claim 68, which is TIFF0007745323000028.tif46169. <Claim 75> The compound The compound of claim 68, which is TIFF0007745323000029.tif48169. <Claim 76> A pharmaceutically acceptable salt of the compound of claims 68 to 75. <Claim 77> A method for treating or inhibiting a disease, comprising administering to an individual having or at risk of developing said disease an amount of at least one poly-N-alkyl substituted glycine or a pharmaceutically acceptable salt thereof, said amount of said poly-N-alkyl substituted glycine being effective to treat or inhibit said disease, said poly-N-alkyl substituted glycine compound having the formula: TIFF0007745323000030.tif7169In formula, B is selected from NH2 and X'; N R X, Y, Z, and X' are independently selected from N-substituted glycine residues comprising N-substituents, wherein the N-substituents of the N-substituted glycine residues are independently selected from naturally occurring α-amino acid side chain moieties, isomers and carbon homologs thereof, and proline residues, and at least one of the N-substituents comprises a halogen atom; n is an integer; and R is the N R N-alkyl substituents of glycine residues, said substituents being from about C4 to about C 20A method for treating or inhibiting a disease wherein the alkyl moiety is selected from the group consisting of: <Claim 78> 78. The method of claim 77, wherein n is 2 and B is NH2. <Claim 79> 78. The method of claim 77, wherein n is 1 and B is X'. <Claim 80> At least one of X and X' is N Lys The method of claim 79, wherein the residue is a hydroxyl group. <Claim 81> The N-alkyl substituent is from about C to about C 18 81. The method of claim 80, wherein the alkyl moiety is selected from the group consisting of linear, branched, and cyclic alkyl moieties of the formula: <Claim 82> X and X' are N Lys The method of claim 81, wherein the residue is a hydroxyl group. <Claim 83> formula The method of claim 82 of TIFF0007745323000031.tif9169. <Claim 84> The alkyl substituent is from about C4 to about C 20 78. The method of claim 77, wherein the alkyl moiety is selected from the group consisting of linear, branched, and cyclic alkyl moieties of the formula: <Claim 85> 78. The method of claim 77, wherein n has a value in the range of 1 to 2. <Claim 86> At least one of the X, Y and Z residues is N Lys and at least one of the N-substituents is chiral. <Claim 87> 78. The method of claim 77, wherein at least one of Y and Z is a proline residue. <Claim 88> 78. The method of claim 77, wherein Y and Z are proline residues. <Claim 89> A is a terminal N-alkyl substituted glycine residue, said alkyl substituent being from C6 to about C 18and n is 1 or 2. <Claim 90> N R is a terminal N-alkyl substituted glycine residue, and the alkyl substituent is from about C to about C 18 and B is selected from the group consisting of N Lys residue and n is 1. <Claim 91> 78. The method of claim 77, wherein the compound is a hexamer. <Claim 92> 78. The method of claim 77, wherein the compound is a 12-mer. <Claim 93> 93. The method of claims 77-92, wherein the halogen-containing moiety comprises a halogen-substituted aryl moiety. <Claim 94> 93. The method of claims 77-92, wherein the halogen-containing moiety comprises a chloro-substituted aryl moiety. <Claim 95> 93. The method of claims 77-92, wherein the halogen-containing moiety comprises a bromo-substituted aryl moiety. <Claim 96> 93. The method of claims 77-92, wherein the halogen-containing moiety comprises an iodo-substituted aryl moiety. <Claim 97> 92. The method of claim 91, wherein each mer in the hexamer contains a halogen-substituted aryl moiety. <Claim 98> 92. The method of claim 91, wherein some of the mers in the hexamer contain halogen-substituted aryl moieties and some of the mers in the hexamer contain non-halogen-containing aryl moieties. <Claim 99> 92. The method of claim 91, wherein exactly one of the mers in the hexamer contains a halogen-substituted aryl moiety. <Claim 100> 93. The method of claim 92, wherein each mer in the hexamer contains a halogen-substituted aryl moiety. <Claim 101> 93. The method of claim 92, wherein some of the mers in the hexamer contain halogen-substituted aryl moieties and some of the mers in the hexamer contain non-halogen-containing aryl moieties. <Claim 102> 93. The method of claim 92, wherein only the first and last mers in the hexamer contain a halogen-substituted aryl moiety. <Claim 103> N R 78. The method of claim 77, wherein at least two of X, Y, Z and X' contain a halogen-containing moiety. <Claim 104> N R 78. The method of claim 77, wherein all of X, Y, Z and X' contain a halogen-containing moiety. <Claim 105> 78. The method of claim 77, wherein the compound is an antibacterial compound. <Claim 106> 78. The method of claim 77, wherein the disease is caused by an enveloped RNA virus. <Claim 107> 78. The method of claim 77, wherein the disease is caused by a coronavirus. <Claim 108> 108. The method of claim 107, wherein the disease is selected from the group consisting of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 19 (COVID-19). <Claim 109> 108. The method of claim 107, wherein the disease is COVID-19. <Claim 110> 13. A method for treating or inhibiting a disease, comprising administering to an individual having or at risk of developing said disease an amount of at least one poly-N-alkyl substituted glycine, or a pharmaceutically acceptable salt thereof, wherein said amount of said poly-N-alkyl substituted glycine is effective to treat or inhibit said disease, and wherein said poly-N-alkyl substituted glycine compound is a compound, or a pharmaceutically acceptable salt thereof, derived from a material selected from the group consisting of the compounds of FIG. 1 and the compounds of FIG. 13 by replacing at least one hydrogen atom in at least one aryl moiety thereof with at least one halogen atom. <Claim 111> 111. The method of claim 110, wherein the compound is derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by substituting at least one para-hydrogen atom in at least one aryl moiety thereof with at least one halogen atom. <Claim 112> 111. The method of claim 110, wherein the compound is derived from a material selected from the group consisting of the compounds of Figure 1 and the compounds of Figure 13 by substituting one hydrogen atom in each aryl moiety thereof with at least one halogen atom. <Claim 113> 113. The method of claim 110, wherein the at least one halogen atom is selected from the group consisting of chlorine, bromine, and iodine. <Claim 114> 113. The method of claim 110, wherein the at least one halogen atom comprises at least a first and a second distinct halogen selected from the group consisting of chlorine, bromine, and iodine. <Claim 115> The compound is The method of claim 110, wherein the image is TIFF0007745323000032.tif46169. <Claim 116> The compound is The method of claim 110, wherein the image is TIFF0007745323000033.tif47169. <Claim 117> The compound is The method of claim 110, wherein the image is TIFF0007745323000034.tif47169. <Claim 118> 111. The method of claim 110, wherein the disease is caused by an enveloped RNA virus. <Claim 119> 111. The method of claim 110, wherein the disease is caused by a coronavirus. <Claim 120> 120. The method of claim 119, wherein the disease is selected from the group consisting of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 19 (COVID-19). <Claim 121> 120. The method of claim 119, wherein the disease is COVID-19. <Claim 122> A method for treating or inhibiting a disease, comprising administering to an individual having or at risk of developing said disease an amount of poly-N-alkyl-substituted glycine or a pharmaceutically acceptable salt thereof, wherein said amount of said poly-N-alkyl-substituted glycine is effective to treat or inhibit said disease, said poly-N-alkyl-substituted glycine compound comprising an N-terminal N-alkyl-substituted glycine residue, said alkyl substituent being from about C4 to about C6. 20 and wherein the C-terminus is selected from NH2, 1 and 2 N-substituted glycine residues, wherein the N-substituents are independently selected from α-amino acid side chain moieties and carbon homologs thereof; and wherein each of the 2 to about 15 monomeric residues between the N-terminus and C-terminus is independently selected from proline residues and N-substituted glycine residues, wherein the N-substituents are independently selected from natural α-amino acid side chain moieties, isomers thereof and carbon homologs thereof, and at least one of the monomeric residues is N Lyswherein at least one of said N-substituents is chiral and said monomeric residues are selected to provide said compound with a non-periodic arrangement of monomeric residues; and at least one of said residues contains at least one halogen. <Claim 123> The N-terminus is an N-alkyl substituted glycine residue, and the alkyl substituent is from about C6 to about C 18 123. The method of claim 122, wherein the alkyl moiety is selected from the group consisting of: <Claim 124> 124. The method of claim 123, wherein the monomer residues comprise 2 to 5 (XYZ) aperiodic trimers. <Claim 125> 125. The method of claim 124, wherein at least one X, Y and Z in each of said trimers is selected to interrupt three-fold periodicity. <Claim 126> 125. The method of claim 124, wherein the monomer residues comprise at least two non-contiguous repeat trimers with at least one residue between them. <Claim 127> At least one X in at least one of said trimers is N Lys residue, and at least one of Y and Z in at least one said trimer is a proline residue. <Claim 128> 123. The method of claim 122, wherein the at least one halogen is selected from the group consisting of bromine, chlorine, and iodine. <Claim 129> 123. The method of claim 122, wherein at least one of the residues comprises at least one halogen-substituted aryl moiety. <Claim 130> 123. The method of claim 122, wherein each of said residues comprises at least one halogen-substituted aryl moiety. <Claim 131> 123. The method of claim 122, wherein some of the residues comprise at least one halogen-substituted aryl moiety and some of the residues comprise at least one non-halogenated substituted aryl moiety. <Claim 132> 132. The method of claim 129, wherein the halogen-substituted aryl moiety is para-substituted. <Claim 133> 132. The method of claim 129, wherein the halogen-substituted aryl moiety is perhalogenated. <Claim 134> 134. The method of claim 122-133, wherein the poly-N-alkyl substituted glycine is a pharmaceutically acceptable salt of a compound of claim 55-66. <Claim 135> 123. The method of claim 122, wherein the disease is caused by an enveloped RNA virus. <Claim 136> 123. The method of claim 122, wherein the disease is caused by a coronavirus. <Claim 137> 137. The method of claim 136, wherein the disease is selected from the group consisting of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 19 (COVID-19). <Claim 138> 137. The method of claim 136, wherein the disease is COVID-19. <Claim 139> A poly-N-substituted glycine compound containing at least one halogen selected from the group consisting of chlorine, bromine and iodine. <Claim 140> 140. The poly-N-substituted glycine compound of claim 139, wherein the poly-N-substituted glycine compound contains at least two halogens selected from the group consisting of chlorine, bromine, and iodine. <Claim 141> 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least two bromine atoms. <Claim 142> 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least two chlorine atoms. <Claim 143> 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least four bromine atoms. <Claim 144> 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least four chlorine atoms. <Claim 145> 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least one para-halogenated aryl group. <Claim 146> 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least two parahalogenated aryl groups. <Claim 147> 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least four parahalogenated aryl groups. <Claim 148> 141. The method of claim 140, wherein said poly-N-substituted glycine compound contains at least one para-chlorinated aryl group. <Claim 149> 140. The method of claim 139, wherein said poly-N-substituted glycine compound contains at least two para-chlorinated aryl groups. <Claim 150> 140. The method of claim 139, wherein said poly-N-substituted glycine compound contains at least four para-chlorinated aryl groups. <Claim 151> 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least one para-brominated aryl group. <Claim 152> 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least two para-brominated aryl groups. <Claim 153> 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least four para-brominated aryl groups. <Claim 154> 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains carboxamide end groups. <Claim 155> 140. The method of claim 139, wherein the poly-N-substituted glycine compound is prepared via rink amide resin.

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Claims

1. A composition containing a certain amount of a poly-N-substituted glycine compound or a pharmaceutically acceptable salt thereof for use as an antibacterial agent for treating infections caused by Gram-positive bacteria, wherein the poly-N-substituted glycine compound contains at least one halogen selected from the group consisting of chlorine, bromine, and iodine; the poly-N-substituted glycine compound is selected from the group consisting of Subgroup I, Subgroup II, and Subgroup III; Subgroup I (I) and in the formula X is selected from the group consisting of fluorine, chlorine, bromine and iodine; n is 3 to 6; Subgroup II (II) where: X is selected from the group consisting of fluorine, chlorine, bromine and iodine; m is 1 to 2; Subgroup III (III) where: X is selected from the group consisting of fluorine, chlorine, bromine and iodine; The compound wherein k is 2 to 3.

2. 2. The composition for use according to claim 1, wherein the poly-N-substituted glycine compound contains at least two halogens selected from the group consisting of chlorine, bromine and iodine.

3. The composition for use according to claim 2, wherein said poly-N-substituted glycine compound contains at least two bromine atoms.

4. The composition for use according to claim 2, wherein said poly-N-substituted glycine compound contains at least two chlorine atoms.

5. The composition for use according to claim 2, wherein said poly-N-substituted glycine compound contains at least four bromine atoms.

6. The composition for use according to claim 2, wherein said poly-N-substituted glycine compound contains at least four chlorine atoms.

7. The composition for use according to claim 2, wherein said poly-N-substituted glycine compound contains at least one para-halogenated aryl group.

8. The composition for use according to claim 1, wherein said poly-N-substituted glycine compound contains at least two parahalogenated aryl groups.

9. The composition for use according to claim 1, wherein said poly-N-substituted glycine compound contains at least four parahalogenated aryl groups.

10. The composition for use according to claim 2, wherein said poly-N-substituted glycine compound contains at least one para-chlorinated aryl group.

11. 2. The composition for use according to claim 1, wherein said poly-N-substituted glycine compound contains at least one para-brominated aryl group.

12. The composition for use according to claim 1, wherein the poly-N-substituted glycine compound contains at least two para-brominated aryl groups.

13. 2. The composition for use according to claim 1, wherein said poly-N-substituted glycine compound contains at least four para-brominated aryl groups.

14. The composition for use according to claim 1, wherein the poly-N-substituted glycine compound is selected from the group consisting of subgroup I.

15. The composition for use according to claim 1, wherein the poly-N-substituted glycine compound is selected from the group consisting of subgroup II.

16. 2. The composition for use according to claim 1, wherein the poly-N-substituted glycine compound is selected from the group consisting of subgroup III.

17. The composition for use according to claim 1, wherein the Gram-positive bacterium is Staphylococcus aureus or Staphylococcus epidermidis.

18. The composition for use according to claim 1, wherein the Gram-positive bacterium is methicillin-resistant Staphylococcus aureus or methicillin-resistant Staphylococcus epidermidis.

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