Halogenated antimicrobial peptoids

Abstract

To provide antimicrobial peptoids.SOLUTION: There is provided herein, a poly-N-substituted glycine compound of a formula, where A is a terminal N-alkyl-substituted glycine residue; n is an integer; B is selected from a group consisting of NH2, one and two N-substituted glycine residues where 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; X, Y and Z are independently selected from a group consisting of N-substituted glycine residues, the N-substituents are independently selected from a 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 bearing moiety.SELECTED DRAWING: Figure 2

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 is hereby incorporated by reference in its entirety.

[0002] 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) for traditional antibiotics, as most bacteria have not evolved resistance to them. DISCLOSURE OF THEINVENTION [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 and 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, probably because such AMPs have evolved with resistance mechanisms designed to evade the AMPs. When bacteria are resistant to certain AMPs through the production of so-called "virulence factors", these virulence factors are molecules that bind to and inactivate certain human AMPs. In general, however, the targets of many AMPs (e.g., bacterial plasma membranes and anionic intracellular macromolecules) are common enough that changes to the AMP sequence can be made to subvert resistance without significant adverse effects on the overall functionality of the AMP.

[0005] Although AMPs have been actively researched for decades, only a few pareticular AMPs have achieved widespread clinical use (e.g., colistin, polymyxin E). This slow clinical adaptation of AMPs is in part due 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 A poly-N-substituted glycine compound of formula TIFF2024170542000002.tif10169, or a pharma- ceutically 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 NH2, 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, their isomers and carbon homologs; 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, their isomers and carbon homologues, 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: A poly-N-alkyl substituted glycine compound of formula TIFF2024170542000003.tif10169, or a pharma- ceutically 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, said N-substituents being independently selected from naturally occurring α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of said N-substituents comprises a halogen atom; n is an integer; and R is the above 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 pharma- ceutically acceptable salt thereof is provided with an N-terminal N-alkyl substituted glycine residue, wherein the alkyl substituent is from about C4 to about C6. 20 and wherein the 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, isomers and carbon homologs thereof; and between said N- and C-terminus, from 2 to about 15 monomeric residues; each of said residues is independently selected from proline residues and N-substituted glycine residues, said N-substituents being independently selected from naturally occurring α-amino acid side chain moieties, isomers and carbon homologs thereof, and at least one of said monomeric residues is N. Lys wherein at least one of said N-substituents is chiral, said monomer residues are selected to provide said compound with a periodic or aperiodic sequence of monomer residues; and at least one of said 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 Figure 13 by replacing at least one hydrogen atom in at least one aryl moiety thereof with at least one halogen atom, or a pharma- ceutically 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 pharma- ceutically 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 TIFF2024170542000004.tif8169, 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, said N-substituents being independently selected from naturally occurring α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of said N-substituents comprises a halogen atom; n is an integer; and R is the above 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 pharma- ceutically 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 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, or a pharma- ceutically acceptable salt thereof.

[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, said poly-N-substituted glycine compound preferably containing carboxamide end groups and preferably prepared via rink amide resin. [Brief description of the drawings]

[0013] Figure 1 shows the molecular structures of first generation peptoids containing halogen atoms. The 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 the 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 mainly free unstructured peptoid chains with a small portion of sheet-like filaments for compounds 19-21 and 24-27, and defined bundles (seen as an increase in scattering intensity and a change in the shape of the curves) for compounds 22 and 23.

[0015] Figure 3 shows the complete SAXS results for the 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 a 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 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 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] FIG. 18 shows the SAXS results for all 10-mers 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 the bundle model (Eq. 6)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] I. Background The aforementioned problems have led to the development of peptidomimetics, which are small protein-like chains designed to mimic peptides. Peptidization 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 peptide isomers in which the side chain is attached to the backbone amide nitrogen instead of the α-carbon. Antimicrobial 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 the corresponding peptides, but often retain antimicrobial activity.

[0026] Peptoids are particularly well suited for AMP mimicry. 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 utilized to impart a wide variety of chemical functionalities to peptoids. As a result, peptoids are highly 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 therapeutics. In particular, there is a need in the art to further improve the antibacterial potency of peptoids without a concomitant increase in cytotoxicity. Similarly, there is a need in the art for a means to reduce the cytotoxicity of existing peptoids without a concomitant decrease in the antibacterial potency of these agents. There is also a need in the art for peptidomimetics with novel substituents that can increase the potency of existing peptoid agents against certain pathogens. Additionally, there is a need in the art for a means to manipulate the aggregate formation ability of peptoids, which may play a role in 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, which are 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 antimicrobial activity of these compositions, while their hemolytic activity is not affected. 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 effect of introducing other halogens into antimicrobial peptoids has not been explored as much.

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

[0031] As a result, chlorinated and brominated analogs of several known peptoids and their shorter counterparts were produced. The shorter brominated analogs showed 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, it is believed that the biological effects of halogen substitution are 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 are becoming less effective in treating cases of infection caused by Gram-positive or Gram-negative superbugs.[5-6] As a result, there is an increasing 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 almost all living organisms and are still considered a promising therapeutic strategy in fighting bacterial infections.[7] AMPs have recently received more attention due to the increase in antimicrobial resistance in many pathogens and the associated 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 side chains are attached to the main chain amide nitrogen rather than the α-carbon.

[10] Antimicrobial 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 antimicrobial peptoids have been produced. Many of these materials have been found to maintain their stability and antimicrobial activity in vivo.

[11]

[0036] Over 4000 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 that contain halogen atoms. To date, fluorination has been of the greatest interest, but studies examining the link 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 analogues led to a decrease in the potency of these analogues, 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 the peptidomimetic sequence and the increased antibacterial activity of these substances against Gram-positive bacteria. This increase in antibacterial activity was achieved without adversely affecting the 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. One of the fluorinated analogues showed similar antibacterial activity to the parent peptide, whereas the chlorinated, brominated and iodinated analogues showed a 2- to 8-fold increase in activity in vitro.

[23] Interestingly, the iodinated analogue had the highest in vitro antibacterial activity, although the chlorinated and brominated versions showed stronger potency in vivo.

[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)4-NH2] is an example of a well-studied promising antimicrobial peptoid with broad-spectrum antibacterial activity, but exhibits a relatively high degree of cytotoxicity in vitro (although it should be noted that peptoid 1 has been tested and found to be reasonably well tolerated in vivo against Staphylococcus aureus in the peritoneal cavity). 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 potency have also been reported. However, incorporation of fluorine or chlorine atoms into the Nspe unit of peptoid 1 was found to not result in 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 result in conformational changes and self-assembly into supramolecular nanostructures, driven by increased hydrophobic interactions. The correlation between antimicrobial activity and self-assembly has been extensively discussed in the literature, where the impact on antimicrobial properties and overall toxicity leans in both directions.[27-28] For example, Xu and co-workers found an association between increased antimicrobial activity and the self-assembly of defined supramolecular nanofibers. On the other hand, Chu-Kung and co-workers found that there was an apparent tendency for fatty acid-bound peptides to show reduced antimicrobial activity.[29-30] Antimicrobial peptoids have a significantly less tendency to fold and form secondary structures, and there appears to be no research directed at the effect of self-assembly on the antimicrobial efficacy of peptoids.

[0043] A structure-activity study of the 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 the halogenated peptoids. The incorporation of halogen atoms into the scaffold of peptoid 1 and its repeating sequence elements was also explored 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 that varied in length (6-, 8-, 10-, 12-mer) and level of halogen substitution (full or alternating). A halogen atom (fluorine, chlorine, bromine or iodine) was introduced via the phenyl ring at position 4 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, 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). Non-halogenated peptoids showed no efficacy against the selected bacterial strains. Thus, compounds 1, 10, 19 and 28 (6mer, 8mer, 10mer and 12mer, respectively) represent inactive controls. Table 1: Minimum inhibitory concentrations (μg / mL) of first-generation peptoids containing halogen atoms. JPEG2024170542000005.jpg214169

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

[0047] Halogenation was found to have no effect on the activity of these peptoids against either E. coli or P. 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 showed significantly increased 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 6-mers showed a >64-fold increase in activity against S. aureus (MICs: >512 μg / ml for 1 and 8 μg / ml for 5) and a 256-fold increase in activity against MRSE (MICs: 512 μg / ml for 1 and 2 μg / ml for 5) with the addition of just three iodine atoms, whereas 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, progressing 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 to their chlorinated and brominated analogues. Compared to the unsubstituted control peptoid, bromination of the 10-mer increased activity against S. aureus by >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 fell under a similar trend but generally showed similar or lower potency. Interestingly, the half-substituted peptoids bearing bromine showed activity comparable to their fully substituted analogues. For example, compound 26 showed an MIC between 1-8 μg / mL compared to 1-4 μg / mL for the fully substituted analogue (compound 22).

[0049] As expected, the hydrophobicity of the peptoids increased with the addition of halogen atoms, with fluorine showing 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, when 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 the peptoids begins 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 compounds tested had a purity of at least 95%. Preparative HPLC was performed using a Waters XSelect Peptide CSH C18 OBDTM, 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 Water 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 Prepl50LC system equipped with a Waters 2489 UV / Visible detector and a Waters Fraction Collector III collector. As stationary phase, 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. 2. General synthesis of peptoids

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

[10] After synthesis, the oligomers were cleaved and deprotected in trifluoroacetic acid (TFA) / triisopropylsilane / water (95:2.5:2.5 (by volume)) 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 the 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 examined. Bacteria grown on agar plates for 18 h at 37°C were diluted to ~1 × 108 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 × 105 CFU / mL in polypropylene 96 U-well microtiter plates (CorningTM 3897; ThermoFisher Scientific, Roskilde) and then incubated 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 (technical triplicates) on different days. 4.X-ray small angle scattering

[0056] SAXS experiments on the 10-mer peptoid were carried out at 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, beams 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). The data set was 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 the automated sample changer.

[40] SAXS data were collected in 10 consecutive frames of 0.5 s 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, Incotec, Germany) and a VÅNTEC-2000 detector. The 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 (gift from David Gram-Naim, Bispebjerg Hospital) was cultured to ~90% confluence after 21–25 h of growth under standard conditions (5% CO2 / 95% O2 at 37 °C). 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 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 test

[0059] Cell viability assessment was performed on 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, using a combination of a free chain and a rectangular fiber characterized by dimensions of a < b < c (where c is the fiber length and a and b are the X and Y directions of the cross-section): TIFF2024170542000006.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 (the 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 a Gaussian chain: TIFF2024170542000007.tif16169 (Formula 2) Here, 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: TIFF2024170542000008.tif12169 (Formula 3) where the amplitude is given by TIFF2024170542000009.tif21169 (Formula 4) and TIFF2024170542000010.tif8169 (Formula 5) Where: TIFF2024170542000011.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: TIFF2024170542000012.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 the scattering for a bundle of parallel cylinders can be calculated using the formula given by Oster and Riley: TIFF2024170542000013.tif27169 (Formula 7) where J0 is the zeroth-order Bessel function and d ijis the distance between the centers of the different cylinders. The above formula gives a general formula that can in principle be evaluated for any collection and number of cylinders. Here, a quadrilateral bundle of cylinders is utilized, and it is assumed that the bundle is 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 TIFF2024170542000014.tif9169 looks like this: TIFF2024170542000015.tif29169 (Formula 8)

[0063] The interactions between peptoid bundles seen at some of the highest concentrations can be modeled using an expression from the Polymer Reference Interaction Site Model (PRISM) given by the structure factors

[44] : TIFF2024170542000016.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] : TIFF2024170542000017.tif18169 (Formula 10) The total expression of intensity is given by: TIFF2024170542000018.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. Nanostructure of peptoids 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 (Eq. 1), while compounds 22 and 23 were fitted using the bundle model (Eq. 6)). The full fit parameters are shown in Tables 2-3 below. Table 2: Full fit parameters for the 10-mer JPEG2024170542000019.jpg175169Table 3: Full fit parameters for fully iodized peptoids with increasing length. JPEG2024170542000020.jpg58169Example 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), and the results are depicted in Figure 3.

[0067] SAXS allows the determination of whether these peptoids self-assemble into nanostructures or instead exist as single molecules in aqueous solution. [33-36] Furthermore, by detailed theoretical modeling, the technique allows for the accurate estimation of the molecular weight and shape, as well as the estimation of the overall physical structure of the peptoid assemblies. The 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 = 4πsin(θ / 2) / λ, where λ is the wavelength of the X-rays and θ is the scattering angle (see Figure 3). It should be noted that 1 / q has the dimension of length and the quantity represents a kind of "measuring stick", with low q probing large structures and high q making SAXS more sensitive to local structures.

[0068] For the 10-mers (compounds 19-27), the scattering curves for the fully brominated and fully iodized peptoids (compounds 22 and 23, respectively) showed significantly higher intensity 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 indicates plate-like fibers. -2 follows a power law of ~q -4 There are no large aggregates that follow a power law of . Fit analysis of these data with a model with a combination of free chains and rectangular fibers resulted in radii of gyration (Rg) for 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 iodized 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 above. Instead, the scattering intensity showed a flat q-dependence at low q, indicating discrete and smaller nanostructures. Data from both compounds can be analyzed using a bundle model, where cylinders representing folded / helical units assemble into trimer / tetramer bundles.

[34] Scattering in the 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 the critical aggregation concentration (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 iodized 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), since more of the 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, since there is still a significant fraction of free peptoid chains that can interact with the bacteria.

[0071] For the fully iodized compound 23, the CAC was found to be much lower, 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 seen by Chu-Kung A. and coworkers. They concluded that a CAC close to the MIC of the free chain in their peptide system leads to a lack of antibacterial activity in the same way that we observed for compound 23.

[29] Example 2

[0072] This example illustrates 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 FIG. 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, which is evident from the retention times in Table 1. However, the detected CAC is still highly correlated with the length of the peptoid. In particular, the CAC of the 6- and 8-mers was lower than the MIC values ​​for these compounds, and therefore, no clear association between CAC and MIC could be established. This is in contrast to the fatty acid-binding peptides studied by Chu-Kung A. and coworkers, who found such a correlation.

[29] Thus, the decrease in activity seen for the 10- and 12-mers seems to be related to their increased hydrophobicity, indicating that there is a threshold at which they remain rather than the self-assembly property itself. However, further studies of the consequences of hydrophobicity and self-assembly with the activity and toxicity of peptoids are 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 could be used as a tool to improve the antibacterial potency of known peptoids, two small libraries of chlorinated and brominated analogs of a well-studied peptoid (peptoid 1) were synthesized (these halogenated analogs showed overall higher potency compared to the fluorinated analogs, while the iodine analogs raised concerns regarding 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 bear halogen atoms) and "half" substitution (every other phenyl ring bears a halogen atom). This strategy resulted in six chloro- and six bromo-modified versions of peptoid 1, depicted in Figure 4.

[0077] The 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 led to an increase in potency, but most caused a loss of activity (see Table 4 below). Judging from the high retention times on the long HPLC, this can 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 a uniform distribution of halogen atoms across the peptoid chain results in higher hydrophobicity compared to allocating chlorine or bromine atoms located at the ends or in the middle of the peptoid sequence. Table 4: MICs (μg / mL) of chlorinated and brominated analogues of peptoid 1. JPEG2024170542000021.jpg102169Example 3

[0078] This example shows the effect of halogenation on the antibacterial activity of a non-active short analog of peptoid 1 (Pep1-6mer).

[0079] As can be seen from the increased values ​​of retention time, hydrophobicity plateaued during the introduction of halogens 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 (truncating 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, while bromination had a more pronounced effect on hydrophobicity than chlorination, similar to that shown by the iodine-containing peptoids. Thus, three brominated short peptoid analogs of heptoid 1 (compounds 49-51) and one non-halogenated peptoid Pep1-6mer were synthesized and tested against the same bacterial strains as the previous peptoid. The data obtained are shown below in Table 5, where the new data set is compared with 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. JPEG2024170542000022.jpg75169

[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 analogue, Pep1-hexamer, by 16-32 fold against both Staphylococcus aureus and Staphylococcus epidermidis. The incorporation of two additional bromine substituents (bringing the total to four) did not significantly affect the activity. On the other hand, the addition of one terminal halogen atom was already sufficient to confer a several-fold increase in antibacterial activity. In contrast to previous data (introduction of halogen did not improve activity against gram-negative bacteria), in this case the addition of two bromines conferred 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 E. coli was reached compared to Pep1-hexamer.

[0081] Since the incorporation of halogens was found to improve the activity of the inactive peptoids, the cytotoxicity profile of the resulting compounds was examined. Peptoid 1, Pep1-6mer and the three brominated analogs were tested against the HaCaT cell line for 1 h. 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 showed 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 showed similar activity and hydrophobicity profiles, initial results indicate a reduced cytotoxicity of the brominated analogues when compared to peptoid 1. V. Conclusion

[0083] The preceding examples demonstrate the effect of fluorine, chlorine, bromine and iodine substitutions on the antimicrobial activity of peptoids. First, the inactive form (NLys-Npm) n Using a peptoid scaffold, it was shown that incorporation of chlorine or bromine could provide improved antibacterial activity against Gram-positive bacteria, although fluorination did not show any significant effect. Introduction of iodine into the 6- and 8-mer analogues dramatically increased activity, but resulted in 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 via the Nspe units 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 analogue of peptoid 1 provided 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 readily modify and alter the physicochemical and antibacterial properties of peptoids, but the effect is highly dependent on the choice of halogen. Moreover, the 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 separate 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, with para-halogenation on peptoid-containing aryl rings being particularly preferred in many applications, although ortho- and meta-substitutions, or even perhalogenation, can be useful in some applications.

[0086] The halogenated compositions described herein may also be alkylated, preferably with terminal alkylation, with alkylation (and especially terminal alkylation) with a C10 or C13 tail being particularly preferred. It has been found that such terminal alkylation can dramatically enhance the antimicrobial activity of peptoids, and in some cases can provide significant antimicrobial activity to peptoids that otherwise have low antimicrobial 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: TIFF2024170542000023.tif8169In formula, A is a terminal N-alkyl substituted glycine residue; n is an integer, B is selected from the group consisting of NH2, 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, their isomers and carbon homologs; X, Y and Z are independently selected from the group consisting of N-substituted glycine residues, said N-substituents being independently selected from the group consisting of natural α-amino acid side chain moieties, their isomers and carbon homologues, and proline residues, and at least one of A, B, X, Y and Z comprises a halogen-containing moiety. The alkyl substituents are preferably from about C4 to about C 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 said 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 a C6 to about C 18 where B is NH and n is 1 or 2. In some embodiments, A is a terminal N-alkyl substituted glycine residue, where the alkyl substituent is from about C to about C 18 where B is selected from the group consisting of N Lys residue, and where n is 1. In some embodiments, the compound may be a 6-mer or a 12-mer.

[0088] In the aforementioned poly-N-substituted glycines, the halogen-containing moiety may be a halogen-substituted aryl moiety, such as, for example, a chloro-substituted aryl moiety, a bromo-substituted aryl moiety, or an iodo-substituted aryl moiety. In some 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 non-halogen-containing aryl moiety. In yet other embodiments, exactly one of the mers 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. The aforementioned poly-N-substituted glycines may contain halogen substitution with any halogen, although substitution with chlorine, bromine, and / or iodine is preferred, and parahalogenation on the aryl moiety on these poly-N-substituted glycines is particularly preferred.

[0089] In some embodiments, the poly-N-substituted glycines may be compounds 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, and more preferably by replacing at least one para-hydrogen atom in at least one aryl moiety thereof with at least one halogen atom. In some embodiments, the compounds are derived from a material selected from the group consisting of the compounds of FIG. 1 and the compounds of FIG. 13 by replacing 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 pharma- ceutically acceptable salts thereof): TIFF2024170542000024.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 a particularly preferred embodiment, 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 utilized 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, a variety of liquid, solid, or multi-state media, such as emulsions, gels, or creams. Such media can include liquid media that may be hydrophobic or may include 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 are: almond oil;babassu oil;borage oil;black currant 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 tricaprylate / 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] A variety of fatty acids can be utilized 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 as injection treatment, or via cell-based drug delivery system.Furthermore, these compositions can be applied in single dose, multiple dose or 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) that contain self-assembled peptoids within the interior of the micelles.

[0095] A variety of counter ions can be utilized in forming pharma-ceutically acceptable salts of the materials disclosed herein.Those skilled in the art will understand that the particular choice of counter ion 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 counter ions such as manganese, magnesium, calcium, etc.

[0096] In certain embodiments, the compositions described herein may be formulated as a mixture of different peptoid compounds. For example, in some embodiments, a mixture of two or more halogenated peptoids of the type disclosed herein may be formed. In other embodiments, a mixture 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. Patent 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 to 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 according to 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 entirety. 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 utilized in the treatment of various diseases caused by various pathogens. These treatments can utilize various other pharmacologic 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] Various terms of illnesses can be treated with the compositions and methodologies disclosed herein. Examples of such illnesses of 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; salmonella infections; shigellosis; typhoid fever; and tularemia; splenic malaria; diphtheria; enterococcal infections; erysipelotrichosis; listeriosis; nocardiosis; pneumococcal infections; staphylococcal infections; streptococcal infections; spirochete infections such as Borrelia burgdorferi, bejel, yaws, and pinta; leptospirosis; Lyme disease; rat-bite fever; relapsing fever; syphilis; actinomycosis; bacteroides; botulism; clostridium 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, those caused by 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. Thus, it is clear that various additions, substitutions, and modifications can be made to the above-described embodiments without departing from the scope of the present invention. Therefore, 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 separately described in certain dependent or independent claims. However, it should be understood that these features can 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 can be combined with each other without departing from the scope of the present disclosure.

[0101] References 1. Bassetti, M.; Merelli, M.; Temperoni, C.; Astilean, A. "New antibiotics for bad bacteria: Where are we?" Ann Clin Microbiol Antimicrob 2013, 12, 22. 2. Mulani,MS; Kamble,EE; Kumkar,SN; Tawre,MS; Pardesi,KR, "New strategies to combat ESKAPE pathogens in the era of antibiotic resistance: A Review." Front Microbiol 2019, 10, 539. 3. Chen, CH; Lu, TK. "Development and challenges of antimicrobial peptides for therapeutic applications." Antibiotics (Basel) 2020, 9 (1). 4. WHO. “Antibacterial drugs of vital importance for human medicine” 6th edition. 5. Dickey, SW; Cheung, GYC; Otto, M., “Multidrugs against bad bacteria: Antivirulence strategies in the era of antibiotic resistance.” Nat Rev Drug Discov 2017, 16 (7), 457-471. 6. Friedman, N.D.; Temkin, E.; Carmeli, Y., "The negative impact of antibiotic resistance." Clin Microbiol Infect 2016, 22 (5), 416-22. 7. Zasloff, M., "Antibacterial peptides in multicellular organisms." Nature 2002, 415 (6870), 389-95. 8. HB Koo, JS "Antimicrobial peptides in clinical investigation" Peptide Science 2019, 111:e24122. 9. Mahlapuu, M.; Hakansson, J.; Ringstad, L.; Bjorn, C., "Antibacterial peptides: an emerging category of therapeutic agents." Front Cell Infect Microbiol 2016, 6, 194. 10. Zuckermann RN, KJ, Kent SBH, Moos WH, "Efficient preparation of peptoids [oligo(N-substituted glycines)] by submonomeric solid-phase synthesis." J Am Chem Soc. 1992, 114 (2). 11. Molchanova, N.; Hansen, P. R.; Franzyk, H., "Advances in the development of antimicrobial peptidomimetics as potential drugs." Molecules 2017, 22 (9). 12. Neumann, CS; Fujimori, DG; Walsh, CT. Halogenation strategies in natural product biosynthesis. Chem Biol 2008, 15 (2), 99-109. 13. Gribble, GW, "Natural Organohalogens: A New Frontier in Pharmaceuticals?" J Chem Educ 2004, 81 (10), 1441-1449. 14. Gimenez, D.; Andreu, C.; del Olmo, M.; Varea, T.; Diaz, D.; Asensio, G., "Introduction of fluorine atoms or trifluoromethyl groups in short cationic peptides enhances their antibacterial activity." Bioorg Med Chem 2006, 14 (20), 6971-8. 15. Meng, H.; Kumar, K., Antibacterial activity and protease stability of peptides containing fluorinated amino acids. 2007, 129 (50), 15615-22. 16. Paulsen, MH; Karlsen, EA; Ausbacher, D.; Anderssen, T.; Bayer, A.; Ochtrop, P.; Hedberg, C.; Haug, T.; Ericson Sollid, JU; Strom, MB, "Amphiphilic cyclic tetrapeptide scaffolds containing halogenated β(2,2)-amino acids with activity against multiresistant bacteria." J Pept Sci 2018, 24 (10), e3117. 17. Gottler, LM; de la Salud Bea, R.; Shelburne, CE; Ramamoorthy, A.; Marsh, EN. Using fluoroamino acids to investigate the effect of altering hydrophobicity on the physical and biological properties of the β-hairpin antimicrobial peptide protegrin-1. Biochemistry 2008, 47 (35), 9243-50. 18. Findlay, B.; Zhanel, GG; Schweizer, F. "Investigating the antimicrobial peptide "window of activity" using cationic lipopeptides with hydrocarbon and fluorinated tails." Int J Antimicrob Agents 2012, 40 (1), 36-42. 19. Molchanova, N.; Hansen, P.R.; Damborg, P.; Nielsen, H.M.; Franzyk, H. "Lysine-based α-peptide / β-peptide mimetics: Influence of hydrophobicity, fluorination, and distribution of cationic charge on antibacterial activity and cytotoxicity." ChemMedChem 2017, 12 (4), 312-318. 20. Molchanova, N.; Hansen, P. R.; Damborg, P.; Franzyk, H. Fluorinated antibacterial lysine-based peptidomimetics with activity against methicillin-resistant Staphylococcus pseudintermedius. J Pept Sci 2018, 24 (7), e3098. 21. Harris, CM; Kannan, R.; Kopecka, H.; Harris, TM. The antibiotic vancomycin--the role of chlorine substituents in the preparation and characterization of monodechlorovancomycin and didechlorovancomycin. Journal of American Chemical Society 1985, 1007 (23), 6652-6658. 22. Groll, M.; Huber, R.; Potts, B. C. "Crystal structures of salinosporamides A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal key consequences of the mechanism of β-lactone ring opening and irreversible binding." J Am Chem Soc 2006, 128 (15), 5136-41. 23. Jia, F.; Zhang, Y.; Zhang, J.; Peng, J.; Zhao, P.; Zhang, L.; Yao, H.; Ni, J.; Wang, K., "Effect of halogenation on the antibacterial activity, antibiotic membrane activity, cytotoxicity and proteolytic stability of the antibacterial peptide Jelleine-I." Peptides 2019, 112, 56-66. 24. Cruz, JC; Iorio, M.; Monciardini, P.; Simone, M.; Brunati, C.; Gaspari,E.; Maffioli, SI; Wellington, E.; Sosio, M.; Donadio, S. Brominated mutants of the lantibiotic NAI-107 with enhanced antibacterial activity. J Nat Prod 2015, 78 (11), 2642-7. 25. Lee, J.; Kang, D.; Choi, J.; Huang, W.; Wadman, M.; Barron, AE; Seo,J. "Effect of side chain hydrophobicity and cationic charge on antibacterial activity and cytotoxicity of helical peptoids." Bioorg Med Chem Lett 2018, 28 (2), 170-173. 26. Gentry, CL; Egleton, RD; Gillespie, T.; Abbruscato, TJ; Bechowski,HB; Hruby,VJ; Davis, TP. Effect of halogenation on blood-brain barrier permeability of novel peptide drugs. Peptides 1999, 20 (10), 1229-38. 27. Haffner SM, MM, "The effect of self-assembly on the performance of antimicrobial peptides." Current Opinion in Colloid & Interface Science 2018, 38, 56-79. 28. Tian, ​​X.; Sun, F.; Zhou, XR; Luo, SZ; Chen, L. "The role of peptide self-assembly in antimicrobial peptides." J Pept Sci 2015, 21 (7), 530-9. 29. Chu-Kung, AF; Nguyen, R.; Bozzelli, KN; Tirrell, M. “Chain length dependence of antimicrobial peptide-fatty acid complex activity.” J Colloid Interface Sci 2010, 345 (2), 160-7. 30. Xu, D.; Jiang, L.; Singh, A.; Dustin, D.; Yang, M.; Liu, L.; Lund, R.; Sellati, TJ; Dong, H., "Designed supramolecular thread-like peptides: Balancing nanostructure, cytotoxicity and antibacterial activity." Chem Commun (Camb) 2015, 51 (7), 1289-92. 31. Frederiksen, N.; Hansen, P. R.; Bjorkling, F.; Franzyk, H., “Peptide / peptoid hybrid oligomers: effect of hydrophobicity and relative side chain length on antibacterial activity and cell selectivity”. Molecules 2019, 24 (24). 32. Chen, Y.; Guarnieri, MT; Vasil, AI; Vasil, ML; Mant, CT; Hodges,RS. "The role of peptide hydrophobicity in the mechanism of action of alpha-helical antimicrobial peptides." Antimicrob Agents Chemother 2007, 51 (4), 1398-406. 33. Schroer MA, SDI "Recent developments in small angle X-ray scattering and hybrid method approaches for biopolymer solutions." New Topics in Life Sciences 2018, 2 (1), 69-79. 34. Lund, R., Shu, J., Xu, T., "Small-angle X-ray scattering study of α-helical bundle-forming peptide-polymer complexes in solution: Chain conformation." Macromolecules 2013, 46 (4), 1625-1632. 35. Narayanan T., WH, "Recent applications of synchrotron radiation and neutrons in soft matter research," Crystallography Reviews 2017, 23 (3), 160-226. 36. Nielsen, JE; Bjornestad, VA; Lund, R. "Uncovering structural interactions between antimicrobial peptides and lipid membranes using small-angle scattering: The case of indolicidin." Soft Matter 2018, 14 (43), 8750-8763. 37. Bacteria, N. cfclsmfdastfbtgaasne M. fdastf 38. Vandecandelaere, I.; Van Nieuwerburgh, F.; Deforce, D.; Nelis, HJ; Coenye, T., Draft genome sequence of methicillin-resistant Staphylococcus epidermidis strain ET-024 isolated from endotracheal tube biofilm in a mechanically ventilated patient. Genome Announc 2014, 2 (3). 39. Pernot, P.; Round, A.; Barrett, R.; De Maria Antolinos, A.; Gobbo, A.; Gordon, E.; Huet, J.; Kieffer, J.; Lentini, M.; Mattenet, M.; Morawe, C.; Mueller-Dieckmann, C.; Ohlsson, S.; Schmid, W.; Surr, J.; Theveneau, P.; Zerrad, L.; McSweeney, S., "Upgraded ESRF BM29 beamline for SAXS on polymers in solution," J Synchrotron Radiat 2013, 20 (Pt 1), 660-4. 40. Round, A.; Felisaz, F.; Fodinger, L.; Godinger, A.; Huet, J.; Villard, C.; Blanchet, C.E.; Pernot, P.; McSweeney, S.; Roessle, M.; Svergun, D.I.; Cipriani, F., "BioSAXS Sample Changer: a fast and reliable robotic sample changer for high-throughput X-ray solution scattering experiments." Acta Crystallogr D Biol Crystallogr 2015, 71 (Pt 1), 67-75. 41. De Maria Antolinos, A.; Pernot, P.; Brennich, ME; Kieffer, J.; Bowler,MW; Delageniere, S.; Ohlsson, S.; Malbet Monaco, S.; Ashton, A.; Franke, D.; Svergun, D.; McSweeney, S.; Gordon, E.; Round, A. "ISPyB for BioSAXS, a gateway to user autonomy in solution scattering experiments," Acta Crystallogr D Biol Crystallogr 2015, 71 (Pt 1), 76-85. 42. Mouritzen, MV; Abourayale, S.; Ejaz, R.; Ardon, CB; Carvalho, E.; Dalgaard, LT; Roursgaard, M.; Jenssen, H., Neurotension, substance P, and insulin enhance cell migration. J Pept Sci 2018, 24 (7), e3093. 43. Nielsen, JE; Bjornestad, VA; Lund, R., "Uncovering structural interactions between antimicrobial peptides and lipid membranes using small-angle scattering: The case of indolicidin." Soft Matter 2018, 14 (43), 8750-8763. 44. Schweizer, K.S., and J.G. Curro, "PRISM theory of structure, thermodynamics, and phase transitions of polymer liquids and alloys." Atomistic Modeling of Physical Properties. Atomistic Modeling of Physical Properties. Springer, Berlin, Heidelberg 1994., 319-377. 44. Arleth L, BM, Pedersen JS, "Small-angle neutron scattering study of the growth behavior, flexibility, and intermicellar interactions of worm-like SDS micelles in aqueous NaBr solutions." Langmuir. 2002, 18 (14), 5343-53.

Claims

1. formula or a pharma- ceutically acceptable salt thereof, wherein A is a terminal N-alkyl substituted glycine residue; n is an integer, B is NH 2 , 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, their isomers and carbon homologs; A poly-N-substituted glycine compound or a pharma- ceutically acceptable salt thereof, wherein X, Y and Z are independently selected from the group consisting of N-substituted glycine residues, said N-substituents being 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.

2. The alkyl substituent is from about C 4 ~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.

3. 2. The compound of claim 1, wherein n has a value in the range of 1 to 3.

4. At least one of the X, Y and Z residues is N Lys and at least one of the N-substituents is chiral.

5. 2. The compound of claim 1, wherein at least one of Y and Z is a proline residue.

6. The compound of claim 1, wherein Y and Z are proline residues.

7. A is a terminal N-alkyl substituted glycine residue, said alkyl substituent being C 6 ~About C 18 and B is selected from the group consisting of a linear alkyl moiety of NH 2and n is 1 or 2.

8. A is a terminal N-alkyl substituted glycine residue, said alkyl substituent being about C 6 ~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.

9. The compound of claim 1 , wherein the compound is a hexamer.

10. The compound of claim 1 , wherein the compound is a 12-mer.

11. The compound of claims 1-10, wherein the halogen-containing moiety comprises a halogen-substituted aryl moiety.

12. The compound of claims 1-10, wherein the halogen-containing moiety comprises a chloro-substituted aryl moiety.

13. The compound of claims 1-10, wherein the halogen-containing moiety comprises a bromo-substituted aryl moiety.

14. The compound of claims 1-10, wherein the halogen-containing moiety comprises an iodo-substituted aryl moiety.

15. 10. The compound of claim 9, wherein each mer in the hexamer contains a halogen-substituted aryl moiety.

16. 10. The compound of claim 9, wherein some of the monomers in the hexamer contain halogen-substituted aryl moieties and some of the monomers in the hexamer contain non-halogen-containing aryl moieties.

17. 10. The compound of claim 9, wherein exactly one of the mers in the hexamer contains a halogen-substituted aryl moiety.

18. The compound of claim 10 , wherein each mer in the hexamer contains a halogen-substituted aryl moiety.

19. 11. The compound of claim 10, wherein some of the monomers in the hexamer contain halogen-substituted aryl moieties and some of the monomers in the hexamer contain non-halogen-containing aryl moieties.

20. 11. The compound of claim 10, wherein only the first and last mers in the hexamer contain a halogen-substituted aryl moiety.

21. 2. The compound of claim 1, wherein at least two of A, B, X, Y and Z contain a halogen-containing moiety.

22. 2. The compound of claim 1, wherein A, B, X, Y and Z all contain a halogen-containing moiety.

23. The compound of claim 1 , wherein the compound is an antibacterial compound.

24. A pharma- ceutically acceptable salt of the compound according to claims 1 to 23.

25. formula or a pharma- ceutically acceptable salt thereof, wherein B is NH 2 and X'; N R X, Y, Z and X' are independently selected from N-substituted glycine residues comprising N-substituents, said N-substituents being independently selected from naturally occurring α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of said N-substituents comprises a halogen atom; n is an integer; and R is the above N R N-alkyl substituents of glycine residues, said substituents being at about C 4 ~About C 20 or a pharma- ceutically acceptable salt thereof.

26. n is 2 and B is NH 2 26. The compound of claim 25,

27. 26. The compound of claim 25, wherein n is 1 and B is X'.

28. At least one of X and X' is N Lys 28. The compound of claim 27, which is a residue.

29. The N-alkyl substituent is from about C 6 ~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:

30. X and X' are N Lys 30. The compound of claim 29, which is a residue.

31. formula The compound according to claim 30.

32. The alkyl substituent is from about C 4 ~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:

33. 26. The compound of claim 25, wherein n has a value in the range of 1 to 2.

34. At least one of the X, Y and Z residues is N Lys and at least one of the N-substituents is chiral.

35. 26. The compound of claim 25, wherein at least one of Y and Z is a proline residue.

36. 26. The compound of claim 25, wherein Y and Z are proline residues.

37. A is a terminal N-alkyl substituted glycine residue, said alkyl substituent being C 6 From about C 18 and B is selected from the group consisting of NH 2 and n is 1 or 2.

38. N R is a terminal N-alkyl substituted glycine residue, said alkyl substituent being about C 6 ~About C 18 and B is selected from the group consisting of N Lys The compound of claim 25 , wherein n is a residue and n is 1.

39. 26. The compound of claim 25, wherein the compound is a hexamer.

40. 26. The compound of claim 25, wherein the compound is a 12-mer.

41. The compound of claims 25-40, wherein the halogen-containing moiety comprises a halogen-substituted aryl moiety.

42. The compound of claims 25-40, wherein the halogen-containing moiety comprises a chloro-substituted aryl moiety.

43. The compound of claims 25-40, wherein the halogen-containing moiety comprises a bromo-substituted aryl moiety.

44. The compound of claims 25-40, wherein the halogen-containing moiety comprises an iodo-substituted aryl moiety.

45. 40. The compound of claim 39, wherein each mer in the hexamer contains a halogen-substituted aryl moiety.

46. 40. The compound of claim 39, wherein some of the monomers in said hexamer contain halogen-substituted aryl moieties and some of the monomers in said hexamer contain non-halogen-containing aryl moieties.

47. 40. The compound of claim 39, wherein exactly one of the mers in the hexamer contains a halogen-substituted aryl moiety.

48. 41. The compound of claim 40, wherein each mer in the hexamer contains a halogen-substituted aryl moiety.

49. 41. The compound of claim 40, wherein some of the monomers in said hexamer contain halogen-substituted aryl moieties and some of the monomers in said hexamer contain non-halogen-containing aryl moieties.

50. 41. The compound of claim 40, wherein only the first and last mers in the hexamer contain a halogen-substituted aryl moiety.

51. N R 26. The compound of claim 25, wherein at least two of X, Y, Z and X' contain a halogen-containing moiety.

52. N R 26. The compound of claim 25, wherein all of X, Y, Z and X' contain a halogen-containing moiety.

53. 26. The compound of claim 25, wherein the compound is an antibacterial compound.

54. A pharma- ceutically acceptable salt of the compound according to claims 25 to 53.

55. A poly-N-substituted glycine compound or a pharma- ceutically acceptable salt thereof, said compound comprising an N-terminal N-alkyl substituted glycine residue, said alkyl substituent being about C 4 ~About C 20 and the C-terminus is selected from linear, branched and cyclic alkyl moieties of 2 and each of the 2 to about 15 monomeric residues between the N-terminus and the C-terminus is independently selected from a proline residue and an N-substituted glycine residue, the N-substituents being 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 an N Lyswherein at least one of said N-substituents is chiral and said monomer residues are selected to provide said compound with a non-periodic arrangement of monomer residues; and at least one of said residues contains at least one halogen, or a pharma- ceutically acceptable salt thereof.

56. The N-terminus is an N-alkyl substituted glycine residue, the alkyl substituent being about C 6 ~About C 18 56. The compound of claim 55, wherein the linear alkyl moiety is selected from the group consisting of:

57. 57. The compound of claim 56, wherein the monomeric residues comprise from 2 to 5 (X-Y-Z) aperiodic trimers.

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.

59. 58. The compound of claim 57, wherein the monomeric residue comprises at least two non-contiguous repeating trimers with at least one residue between them.

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 of said trimers is a proline residue.

61. 56. The compound of claim 55, wherein the at least one halogen is selected from the group consisting of bromine, chlorine and iodine.

62. 56. The compound of claim 55, wherein at least one of the residues comprises at least one halogen-substituted aryl moiety.

63. 56. The compound of claim 55, wherein each of said residues comprises at least one halogen-substituted aryl moiety.

64. 56. The compound of claim 55, wherein some of said residues comprise at least one halogen substituted aryl moiety and some of said residues comprise at least one non-halogenated substituted aryl moiety.

65. The compound of claims 62-64, wherein the halogen substituted aryl moiety is para substituted.

66. The compound of claims 62-64, wherein the halogen-substituted aryl moiety is perhalogenated.

67. A pharma- ceutically acceptable salt of the compound according to claims 55 to 66.

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.

69. 69. The compound of claim 68, derived from a material selected from the group consisting of the compounds of Figures 1 and 13 by replacing at least one parahydrogen atom in at least one aryl moiety thereof with at least one halogen atom.

70. 69. The compound of claim 68, derived from a material selected from the group consisting of the compounds of Figures 1 and 13 by replacing one hydrogen atom in each aryl moiety thereof with at least one halogen atom.

71. 71. The compound of claims 68-70, wherein the at least one halogen atom is selected from the group consisting of chlorine, bromine and iodine.

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.

73. The compound .

69. The compound of claim 68, wherein:

74. The compound 69. The compound of claim 68,

75. The compound 69. The compound of claim 68, wherein:

76. A pharma- ceutically acceptable salt of a compound of claims 68-75.

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 pharma- ceutically 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: During the ceremony, B is NH 2 and X'; N R X, Y, Z and X' are independently selected from N-substituted glycine residues comprising N-substituents, said N-substituents being independently selected from naturally occurring α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of said N-substituents comprises a halogen atom; n is an integer; and R is the above N R N-alkyl substituents of glycine residues, said substituents being at about C 4 ~About C 20 The method for treating or inhibiting a disease wherein the alkyl moiety is selected from the group consisting of linear, branched and cyclic alkyl moieties of the formula:

78. n is 2 and B is NH 2 78. The method of claim 77, wherein:

79. 78. The method of claim 77, wherein n is 1 and B is X'.

80. At least one of X and X' is N Lys The method of claim 79, wherein the amino acid is a residue.

81. The N-alkyl substituent is from about C 6 ~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.

82. X and X' are N Lys The method of claim 81, wherein the amino acid is a residue.

83. formula 83. The method of claim 82.

84. The alkyl substituent is from about C 4 ~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.

85. 78. The method of claim 77, wherein n has a value in the range of 1 to 2.

86. At least one of the X, Y and Z residues is N Lys and at least one of the N-substituents is chiral.

87. 78. The method of claim 77, wherein at least one of Y and Z is a proline residue.

88. 78. The method of claim 77, wherein Y and Z are proline residues.

89. A is a terminal N-alkyl substituted glycine residue, said alkyl substituent being C 6 From about C 18 and B is selected from the group consisting of NH 2 and n is 1 or 2.

90. N R is a terminal N-alkyl substituted glycine residue, said alkyl substituent being about C 6 ~About C 18 and B is selected from the group consisting of N Lys The method of claim 77, wherein n is a residue and n is 1.

91. 78. The method of claim 77, wherein the compound is a hexamer.

92. 78. The method of claim 77, wherein the compound is a 12-mer.

93. The method of claims 77-92, wherein the halogen-containing moiety comprises a halogen-substituted aryl moiety.

94. The method of claims 77-92, wherein the halogen-containing moiety comprises a chloro-substituted aryl moiety.

95. The method of claims 77-92, wherein the halogen-containing moiety comprises a bromo-substituted aryl moiety.

96. The method of claims 77-92, wherein the halogen-containing moiety comprises an iodo-substituted aryl moiety.

97. 92. The method of claim 91 , wherein each mer in the hexamer contains a halogen-substituted aryl moiety.

98. 92. The method of claim 91, wherein some of the mers in said hexamer contain halogen-substituted aryl moieties and some of the mers in said hexamer contain non-halogen-containing aryl moieties.

99. 92. The method of claim 91 , wherein exactly one of the mers in the hexamer contains a halogen-substituted aryl moiety.

100. 93. The method of claim 92, wherein each mer in the hexamer contains a halogen-substituted aryl moiety.

101. 93. The method of claim 92, wherein some of the mers in said hexamer contain halogen-substituted aryl moieties and some of the mers in said hexamer contain non-halogen-containing aryl moieties.

102. 93. The method of claim 92, wherein only the first and last mers in the hexamer contain a halogen-substituted aryl moiety.

103. N R 78. The method of claim 77, wherein at least two of X, Y, Z and X' contain a halogen-containing moiety.

104. N R 78. The method of claim 77, wherein all of X, Y, Z and X' contain a halogen-containing moiety.

105. 78. The method of claim 77, wherein the compound is an antibacterial compound.

106. 78. The method of claim 77, wherein the disease is caused by an enveloped RNA virus.

107. 78. The method of claim 77, wherein the disease is caused by a coronavirus.

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).

109. The method of claim 107, wherein the disease is COVID-19.

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 pharma- ceutically 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 being a compound 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, or a pharma- ceutically acceptable salt thereof.

111. 111. The method of claim 110, wherein said compound is 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 parahydrogen atom in at least one aryl moiety thereof with at least one halogen atom.

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 replacing one hydrogen atom in each aryl moiety thereof with at least one halogen atom.

113. The method of claims 110-112, wherein the at least one halogen atom is selected from the group consisting of chlorine, bromine and iodine.

114. The method of any one of claims 110 to 112, 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.

115. The compound is The method of claim 110, wherein:

116. The compound is The method of claim 110, wherein:

117. The compound is The method of claim 110, wherein:

118. 111. The method of claim 110, wherein the disease is caused by an enveloped RNA virus.

119. 111. The method of claim 110, wherein the disease is caused by a coronavirus.

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).

121. The method of claim 119, wherein the disease is COVID-19.

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 pharma- ceutically 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 comprising an N-terminal N-alkyl substituted glycine residue, said alkyl substituent being about C 4 ~About C 20 and the C-terminus is selected from linear, branched and cyclic alkyl moieties 2 and each of the 2 to about 15 monomeric residues between the N-terminus and the C-terminus is independently selected from a proline residue and an N-substituted glycine residue, the N-substituents being 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 an N Lys wherein 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.

123. The N-terminus is an N-alkyl substituted glycine residue, the alkyl substituent being about C 6 ~About C 18 The method of claim 122, wherein the alkyl moiety is selected from the linear alkyl moieties:

124. 124. The method of claim 123, wherein the monomeric residues comprise from 2 to 5 (X-Y-Z) aperiodic trimers.

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.

126. 125. The method of claim 124, wherein the monomeric residue comprises at least two non-contiguous repeat trimers having at least one residue between them.

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 of the trimers is a proline residue.

128. 123. The method of claim 122, wherein the at least one halogen is selected from the group consisting of bromine, chlorine and iodine.

129. 123. The method of claim 122, wherein at least one of the residues comprises at least one halogen-substituted aryl moiety.

130. 123. The method of claim 122, wherein each of the residues comprises at least one halogen-substituted aryl moiety.

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.

132. The method of claims 129-131, wherein the halogen substituted aryl moiety is para substituted.

133. The method of claims 129-131, wherein the halogen-substituted aryl moiety is perhalogenated.

134. The method of claims 122-133, wherein the poly-N-alkyl substituted glycine is a pharma- ceutically acceptable salt of a compound of claims 55-66.

135. 123. The method of claim 122, wherein the disease is caused by an enveloped RNA virus.

136. 123. The method of claim 122, wherein the disease is caused by a coronavirus.

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).

138. The method of claim 136, wherein the disease is COVID-19.

139. A poly-N-substituted glycine compound containing at least one halogen selected from the group consisting of chlorine, bromine and iodine.

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.

141. 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least two bromine atoms.

142. 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least two chlorine atoms.

143. 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least four bromine atoms.

144. 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least four chlorine atoms.

145. 141. The method of claim 140, wherein the poly-N-substituted glycine compound contains at least one para-halogenated aryl group.

146. 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least two para-halogenated aryl groups.

147. 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least four para-halogenated aryl groups.

148. 141. The method of claim 140, wherein said poly-N-substituted glycine compound contains at least one para-chlorinated aryl group.

149. 140. The method of claim 139, wherein said poly-N-substituted glycine compound contains at least two para-chlorinated aryl groups.

150. 140. The method of claim 139, wherein said poly-N-substituted glycine compound contains at least four para-chlorinated aryl groups.

151. 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least one para-brominated aryl group.

152. 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least two para-brominated aryl groups.

153. 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains at least four para-brominated aryl groups.

154. 140. The method of claim 139, wherein the poly-N-substituted glycine compound contains carboxamide end groups.

155. 140. The method of claim 139, wherein the poly-N-substituted glycine compound is prepared via rink amide resin.

Images