Halogenated antimicrobial peptoids

Abstract

We provide antimicrobial peptoids. [Solution] Formula TIFF2026143571000036.tif6169 The present invention provides a poly-N-substituted glycine compound in which A is a terminal N-alkyl-substituted glycine residue; n is an integer; B is selected from the group consisting of NH2, 1 and 2 N-substituted glycine residues, the 1 and 2 N-substituted glycine residues having N-substituteds independently selected from the group consisting of natural 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, the N-substituteds are independently selected from the group consisting of natural α-amino acid side chain moieties, their isomers and carbon homologs, and at least one of A, B, X, Y and Z contains a halogen-containing moiety.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Application No. 62 / 841,227, filed on April 30, 2019, which has the same title and the same inventors, and which is incorporated herein by reference in its entirety.

[0002] This disclosure generally relates 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 defend a wide range of organisms against bacterial pathogens. These peptides show potential as supplements (or alternatives) to conventional antibiotics, as most bacteria have not evolved resistance to them. [Disclosure of the Invention] [Problems that the invention aims to solve]

[0004] AMPs destroy bacteria in various ways. Some AMPs kill bacteria by permeating the cytoplasmic membrane and causing depolarization or leakage of endocellular material. Other AMPs function by targeting anionic bacterial components such as DNA, RNA, or cell wall components. Bacterial resistance to AMPs is rare, which is likely because such AMPs have evolved along with resistance mechanisms designed to evade them. When bacteria exhibit resistance to certain AMPs through the production of so-called "toxic factors," these toxic factors are molecules that bind to certain human AMPs and inactivate them. However, generally speaking, the targets of many AMPs (e.g., bacterial plasma membranes and anionic intracellular macromolecules) are common enough that alterations to the AMP sequence can be made to disrupt resistance without significantly adversely affecting the overall functionality of the AMP.

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

[0006] In one aspect, the formula A poly-N-substituted glycine compound of TIFF2026143571000002.tif10169, or a pharmaceutically acceptable salt thereof, is provided, in the 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, the one and two N-substituted glycine residues having N-substituteds independently selected from the native α-amino acid side chain moiety, its isomers and carbon homologs, and X, Y, and Z are independently selected from the group consisting of N-substituted glycine residues, and the N-substituents are independently selected from the group consisting of native α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of A, B, X, Y, and Z contains a halogen-containing moiety (or supported moiety).

[0007] In another embodiment, the formula is: A poly-N-alkyl-substituted glycine compound of TIFF2026143571000003.tif10169, or a pharmaceutically acceptable salt thereof, is provided, in the formula B is selected from NH2 and X'; N RX, Y, Z, and X' are independently selected from N-substituted glycine residues containing N-substituents, the N-substituents of the N-substituted glycine residues are independently selected from the native α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of the N-substituents contains a halogen atom; n is an integer; and R is the same as N R The N-alkyl substituent of the glycine residue, and the substituent is approximately C4 to approximately C 20 Selected from linear, branched, and cyclic alkyl moieties.

[0008] In a further embodiment, poly-N-substituted glycine or a pharmaceutically acceptable salt thereof is provided comprising an N-terminal N-alkyl-substituted glycine residue, where the alkyl substituent is approximately C4 to approximately C4 20 Selected from the linear, branched, and cyclic alkyl moieties; the C-terminus is NH2, selected from one and two N-substituted glycine residues, the N-substituents being the α-amino acid side chain moiety and its carbon homolog; and independently selected from 2 to about 15 monomer residues between the N- and C-terminuses; each of the residues is independently selected from a proline residue and an N-substituted glycine residue, the N-substituents are independently selected from the native α-amino acid side chain moiety, its isomers, and carbon homologs, and at least one of the monomer residues is N Lys The compound is composed of at least one N-substituent which is chiral, and the monomer residues are selected to give the compound a periodic or aperiodic sequence of monomer residues; and at least one of the residues which contains at least one halogen substituent.

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

[0010] In yet another aspect, provided is a method for treating or inhibiting a disease, the method comprising administering to an individual having the disease or at risk of developing the disease an amount of at least one poly-N-alkyl substituted glycine or a pharmaceutically acceptable salt thereof, wherein the amount of said poly-N-alkyl substituted glycine is effective for treating or inhibiting the disease, and said poly-N-alkyl substituted glycine compound has the formula TIFF2026143571000004.tif8169, wherein B is selected from NH2 and X'; N R , X, Y, Z and X' are each independently selected from N-substituted glycine residues comprising an N-substituent, said N-substituent of said N-substituted glycine residue is each independently selected from naturally occurring α-amino acid side chain moieties, isomers and carbon homologs thereof, and proline residues, and at least one of said N-substituents comprises a halogen atom; n is an integer; and R is the N-alkyl substituent of said N R glycine residue, and said substituent is selected from linear, branched and cyclic alkyl moieties of from about C4 to about C 20 .

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

[0012] In yet another aspect, there is provided a poly-N-substituted glycine compound containing at least one halogen selected from the group consisting of chlorine, bromine and iodine. The poly-N-substituted glycine compound preferably comprises a carboxamide end group, and is preferably produced via a link amide resin. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0014] Figure 2 is a set of graphs of small-angle X-ray scattering (SAXS) data showing scattering intensity plotted against the modulus of scattering vector Q for a 10-mer peptoid at 5 mg / ml and 37°C obtained at the BM29 beamline in the ESRF laboratory. Figure 2A shows the results for fully halogenated peptoids, while Figure 2B shows the results for semi-halogenated peptoids. Non-halogenated peptoid (Compound 19) is included in both graphs as a reference. The results show mainly free unstructured peptoid chains with small segments 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 curve) for Compounds 22 and 23.

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

[0016] Figure 4 shows chlorinated and brominated mutants of peptoid 1 [H-(NLys-Nspe-Nspe)4-NH2], as well as a shortened brominated peptoid 1 analog.

[0017] Figure 5 shows the IC50 curves of selected peptoids for HaCaT cell lines.

[0018] Figure 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] Figures 7–12 show the structures of some specific non-limiting examples of halogenated analogs of peptoid 1.

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

[0021] Figures 14–16 show the structures of some specific, non-limiting examples of halogenated analogs of peptoids, the structure of which is shown in Figure 17.

[0022] Figure 17 is a graph illustrating the cytotoxicity (HaCaT cell lines) of several peptoids disclosed herein.

[0023] Figure 18 shows the SAXS results for all decamers measured by ESRF at the indicated concentrations, along with the model fit (data for compounds 19-21 and 24-27 were fitted using a model for random polymer-like chains with a fibrous cluster model (Equation 1), while data for compounds 22 and 23 were fitted using a bundle model (Equation 6)). [Modes for carrying out the invention]

[0024] I. Background The aforementioned problems led to the development of peptide mimetics, which are small protein-like chains designed to mimic peptides. Peptidization can be performed by denaturing existing peptides. Peptid mimetics can also be based on similar systems that mimic peptides (e.g., peptoids and β-peptides).

[0025] Peptoids (oligomers of N-substituted glycine) are isomers of peptides in which the side chain is bonded to the amide nitrogen of the main chain rather than to 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 their corresponding peptides, while often retaining antimicrobial activity.

[0026] Peptoids are particularly well-suited for AMP mimicry. Peptoids are readily synthesized using conventional peptide synthesizers, providing access to a diverse range of sequences at relatively low cost. Submonomer synthesis methods are known that can be used to confer 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 designed to form amphiphilic helices that resist heat and chaotropic denaturation.

[0027] Despite their potential, further improvements to peptoids are needed for these substances to achieve their full potential as antimicrobial agents. In particular, there is a need in the art to further improve the antimicrobial efficacy of peptoids without incidentally increasing cytotoxicity. Similarly, there is a need in the art for means to reduce the cytotoxicity of existing peptoids without incidentally reducing their antimicrobial efficacy. Furthermore, there is a need in the art for peptide mimes with novel substituents that can increase the efficacy of existing peptoid substances against specific pathogens. In addition, there is a need in the art for means to manipulate the aggregation ability of peptoids, which may be related to the pharmaceutically effectiveness of these substances.

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

[0029] Recently, it has been shown that incorporating fluorine atoms into certain peptide mimes can improve the antimicrobial activity of these compositions without affecting their hemolytic activity. 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 peptide mimes has been found to have a significant effect on the activity of these substances against Gram-positive bacteria. However, the effects of introducing other halogens into antimicrobial peptoids have not been explored as much.

[0030] These researchers have addressed this problem by synthesizing a library of halogenated peptoids. These peptoids contain one or more fluorine, chlorine, bromine, and / or iodine atoms, varying in length and level of halogen substitution at the 4-position of the phenyl ring. In these materials, a clear correlation was observed between halogenation of inactive model peptoids and the resulting increase in their antimicrobial activity.

[0031] As a result, chlorinated and brominated analogs of several known peptoids and their shorter counterparts were generated. These shorter brominated analogs showed significant improvement in activity against Staphylococcus aureus (up to 32-fold) and similarly significant improvement in activity against Escherichia coli and Pseudomonas aeruginosa (16-64-fold). In many cases, these improvements in efficacy were achieved while also achieving a reduction in cytotoxicity.

[0032] While we do not wish to be bound by theory, the biological effects of halogen substitution are thought to be related to the relative hydrophobicity and self-assembly properties of the resulting compounds. Small-angle X-ray scattering (SAXS) suggests that the self-assembly 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 will be described in more detail below, these features correlate with the activity of these peptoids. II. Overview

[0033] The rapid emergence and widespread distribution of antibacterial resistance is recognized as one of the most serious global threats to human health.[1-4] Most antibiotics currently in clinical use are proving 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 field for novel antibiotics or alternative therapies that can be used to treat these pathogens.

[0034] Antimicrobial peptides (AMPs) are essential components of the innate immune system in almost all living organisms and remain a promising therapeutic strategy in combating bacterial infections. [7] AMPs have recently attracted more attention due to the increasing antibiotic resistance in many pathogens and the resulting need for new antibiotics. As a result, 36 different AMPs are currently undergoing clinical trials for various infectious diseases. [8] However, the practical application of AMPs is limited by the rapid in vivo degradation of these substances and concerns about systemic toxicity. Currently, the manufacturing costs of these materials are also prohibitively expensive. [9]

[0035] Poly-N-substituted glycines (peptoids) are a type of peptide mimetic in which the side chain is bonded 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, various antimicrobial peptoids have been produced. Many of these substances have been found to maintain their stability and antimicrobial activity in vivo.

[11]

[0036] More than 4,000 halogenated compounds have been isolated from natural sources. Natural products of this diverse group exhibit a wide range of biological activities, including anticancer and antimicrobial properties.[12-13] However, until recently, limited attention has been paid to confirming the antimicrobial properties of peptides and peptide mimes containing halogen atoms. To date, fluorination is of the most interesting interest, but studies investigating the relationship between fluorination and antimicrobial activity have not yielded conclusive results.

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

[0038] Recently, Molchanova et al. reported a link between the introduction of fluorine atoms into peptide mimetic sequences and an increase in the antimicrobial activity of these substances against Gram-positive bacteria. This increase in antimicrobial activity was achieved without adverse effects on hemolytic properties. [19-20] Similarly, both vancomycin and salinosporamide A have been found to require the presence of one to two chlorine substituents to achieve their antimicrobial activity. [21-22]

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

[23] Interestingly, the chlorinated and brominated versions showed more potent efficacy in vivo, but the iodized analog exhibited the highest in vitro antimicrobial activity.

[0040] Both chlorinated and brominated variants of the antibiotic NAI-107 showed higher antimicrobial activity, although the brominated variant showed slightly higher efficacy.

[24]

[0041] The dodecamer peptoid 1 [H-(NLys-Nspe-Nspe)4-NH2] is a well-studied and promising antimicrobial peptoid with broad antimicrobial activity, although it exhibits relatively high cytotoxicity in vitro (however, it should be noted that peptoid 1 has been tested and found to be reasonably resistant to Staphylococcus aureus in the peritoneal cavity in vivo). See Czyzewski et al. (2016) In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents, PLoS ONE, 11(2): e0135961 doi:10.1371 / journal.pone.0135961. PMCID: 26849681. Recent attempts to enhance the antimicrobial activity by altering the structure of peptoid 1 have also been reported. However, the incorporation of fluorine or chlorine atoms into the Nspe unit of peptoid 1 was found not to result in a significant improvement in the antimicrobial profile of the compound.

[25]

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

[26] This can lead to conformational changes and self-assembly into supramolecular nanostructures, driven by increased hydrophobic interactions. The correlation between antimicrobial activity and self-assembly has been extensively discussed in the literature, where the effects on antimicrobial properties and overall toxicity tend in both directions. [27-28] For example, Xu and collaborators found a correlation between increased antimicrobial activity and the self-assembly of defined supramolecular nanofibers. On the other hand, Chu-Kung and collaborators found a clear tendency for fatty acid-binding peptides to exhibit decreased antimicrobial activity. [29-30] Antimicrobial peptoids are significantly less likely to fold and form secondary structures, and there appear to be no studies directed toward the effect of self-assembly on the antimicrobial efficacy of peptoids.

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

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

[0045] All 36 peptoids were tested against seven bacterial strains. These included 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). The non-halogenated peptoids showed no efficacy against the selected bacterial strains. Therefore, compounds 1, 10, 19, and 28 (6mer, 8mer, 10mer, and 12mer, respectively) represent inactive controls. Table 1: Minimum inhibitory concentration (μg / mL) of first-generation peptoids containing halogen atoms TIFF2026143571000005.tif214169

[0046] The 36 compounds are divided into four sets according to their length. Each set contains an unsubstituted control, four peptoids completely substituted with fluorine, chlorine, bromine, or iodine, and four "partially substituted" peptoids (where every other phenyl ring is substituted with a halogen atom).

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

[0048] The "half-substituted" sets showed a similar trend of decreased potency, but generally exhibited similar or lower potency. Interestingly, the half-substituted peptoids containing bromine showed activity comparable to their fully substituted analogues. For example, compound 26 showed an MIC between 1 and 8 μg / mL, compared to 1–4 μg / mL for its 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 iodine incorporation resulted in a significantly higher hydrophobic profile. In parallel, the antimicrobial activity of the peptoids showed a well-established correlation, where increased hydrophobicity led to increased antimicrobial activity. However, when a certain hydrophobic threshold was met (e.g., for compounds 23 and 32), activity was lost. This phenomenon has been previously observed in other peptide / peptoid studies. [31-32] Overall, the introduction of halogen atoms was found to result in increased hydrophobicity and increased antimicrobial activity against Gram-positive bacteria. However, beyond a certain hydrophobic threshold, the activity of the peptoids began to decrease.

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

[0051] The starting materials and solvents were purchased from commercial suppliers (Iris Biotech, Sigma-Aldrich, and Merck) and used without further purification. The water used for analysis 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 Waters Symmetry C18, 5 μm, 4.6 mm × 250 mm. An aqueous acetonitrile (MeCN) gradient with 0.1% trifluoroacetic acid (TFA) was used (eluent A: 5:95 MeCN-H2O + 0.1% TFA, eluent B: 95:5 MeCN-H2O + 0.1% TFA). All tested compounds had a purity of at least 95%. Preparative HPLC was performed using a Waters XSelect Peptide CSH C18 OBD™, 5 μm, 19 mm × 250 mm column and the same eluents as used for analytical HPLC. High-resolution mass spectrometer (HRMS) spectra were obtained using a Waters QTOF Premier mass spectrometer equipped with an electrospray ionization source and quadrupole and time-of-flight MS detectors.

[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 (pore size 300 Å (angstroms), particle size 1.7 μm, 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. Purification by preparative HPLC was performed using a Waters Prepl50LC system equipped with a Waters 2489 UV / Visable detector and a Waters Fraction Collector III collector. As the stationary phase, a Waters XBridge BEH300 Prep C18 column (5 μm particle size, 19 mm × 10 mm) was used, which contained a Waters XBridge Peptide BEH300 C18 VanGuard column (5 μm particle size, 19 mm × 100 mm). 2. General synthesis of peptoids

[0054] All peptoids were manually synthesized on linkamide 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 (volume ratio)) for 30 minutes. 3. Measurement of the minimum inhibitory concentration

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

[37] The antibacterial activity of peptoids against biofilms producing Staphylococcus aureus ATCC 25923, ATCC 29213, and methicillin-resistant Staphylococcus aureus USA 300, methicillin-resistant Staphylococcus epidermidis ATCC 51625, methicillin-resistant Staphylococcus epidermidis ET-02438, Pseudomonas aeruginosa Pa01(H103), and Escherichia coli ATCC 25922 was investigated. Bacteria grown on agar plates at 37°C for 18 hours were diluted to ~1 × 10⁸ CFU / mL in Mueller-Hinton medium II (MHB II). To achieve a final concentration of 5 × 10⁵ CFU / mL in polypropylene 96 U-well microtiter plates (Corning™ 3897; ThermoFisher Scientific, Roskilde), bacteria were inoculated into a 2-fold serial dilution of peptoid in MHB II and then incubated in ambient air at 37°C for 18 hours. The MIC value was determined as the lowest concentration at which no visible bacterial growth was observed. The experiment was performed twice (technically three times) on different days. 4.X-ray small angle scattering

[0056] SAXS experiments with decameral peptoids were performed on the automated BM29 bioSAXS beamline at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France.

[39] Using an energy of 12.5 keV and a detector spacing of 2.87 m, data was obtained 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). Datasets were calibrated to an absolute intensity scale using water as the primary standard. Samples (40 μL) were passed through a capillary using the flow mode of an automated sample changer.

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

[41]

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

[0058] Immortalized human keratinocyte (HaCaT) cell lines (a gift from David Gramnaim of Bispevjerg Hospital) were grown under standard conditions (37°C, 5% CO2 / 95% O2) for 21–25 hours, and then cultured to ~90% confluence. Cells were cultured in Dulbecco's modified Eagle medium supplemented with 10% (v / v) fetal bovine serum (FBS). Penicillin (100 IU / mL) and streptomycin (100 μg / mL) were added to all culture media. 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 measurement 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 peptoid (concentrations ranging from 0 to 1000 μg / mL) dissolved in the same medium used for culturing the cell line at 37°C for 1 hour. The cells were then washed twice with PBS at 37°C. A 100 μL aliquot of 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, followed by incubation at 37°C for 1 hour 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 test compound were used as a negative control. Data were obtained in three independent biological replicates, which were performed on separate passages of cells and on separate days, for a total of six replicates. 7. Theoretical Modeling of Data from SAXS a. Random polymer-like chains with fibrillar clusters

[0060] To extract accurate and detailed structural information, SAXS data for pure peptoid chains were analyzed using Equation 1 below, with a combination of free chains and rectangular fibers characterized by dimensions a < b < c (where c is the length of the fiber, and a and b are the X and Y directions of the cross-section): TIFF2026143571000006.tif16169(Equation 1)

[43] . where φ is the volume fraction of the polymer, V p is the volume of the polymer, Δρ is the excess scattering length density, fchain This is the fraction of the free chain. p (Average number of peptides in each sheet) is N p =abc / V p It is defined as P chain (q) is the shape factor of a free peptoid chain, given by the Debye equation for a Gaussian chain: TIFF2026143571000007.tif16169 (Formula 2) Here, R g This is the radial rotation of the peptoid chain.

[0061] Assuming the length of the peptoid sheet is much larger than their lateral dimensions (i.e., c >> a, b), the shape factor P sheet (q) is given by the following equation: TIFF2026143571000008.tif12169 (Formula 3) Here, the amplitude is given by the following equation. TIFF2026143571000009.tif21169 (Formula 4) and TIFF2026143571000010.tif8169 (Formula 5) Here, TIFF2026143571000011.tif10169b. Self-assembled peptides in solution: Peptide cylindrical bundle model

[0062] Each peptoid in the bundle is approximated as a simple solid cylinder given by the following equation: TIFF2026143571000012.tif26169 (Formula 6) Here, L is the total length of the cylinder, R is the radius, and α is the angle between the momentum transfer vector q and the cylinder axis parallel to L. J1 is the first-order Bessel function. The shape factor describing scattering for a bundle of parallel cylinders can be calculated using the equation given by Oster and Riley: TIFF2026143571000013.tif27169 (Formula 7) Here, J0 is the zero-order Bessel function, and dij is the distance between the centers of different cylinders. The above formula gives a general formula that can, in principle, be evaluated for any set and number of cylinders. Here, a quadrilateral bundle of cylinders is used, and it is assumed that the bundle is arranged in a square where the center of each cylinder is located at each corner. Thus, all distances between cylinders are d = 2fR, except for the diagonal distances, where d = √8fR, and in the formula, f is the expansion coefficient that adjusts the distances between cylinders. Equation 7 is the shape factor, P(q) cyl It can be rewritten in relation to the structural factor TIFF2026143571000014.tif9169 will look like this: TIFF2026143571000015.tif29169 (Formula 8)

[0063] Interactions between peptoid bundles observed at some of the highest concentrations can be modeled using representations from the polymer reference interaction site (PRISM) model, which is given by the structural factor

[44] : TIFF2026143571000016.tif13169 (Formula 9) Here, ν is a measure of the excluded volume, and c(q) is the shape factor of an infinitely thin rod.

[45] TIFF2026143571000017.tif18169 (Formula 10) The total representation of intensity is given by the following equation: TIFF2026143571000018.tif18169 (Formula 11) Here, f agg φ is the proportion of peptoid chains assembled into a bundle. CAC =φ-(f agg This enables the calculation of CAC from *φ). C. Peptoid nanostructure in solution SAXS results

[0064] Figure 18 shows the complete SAXS results for all decamers measured by ESRF at the indicated concentrations, along with the model fit (compounds 19-21 and 24-27 were fitted using random polymer-like chains with a fibrous cluster model (Equation 1), while compounds 22 and 23 were fitted using a bundle model (Equation 6)). The full fit parameters are shown in Tables 2-3 below. Table 2: Full-fit parameters for the decamer TIFF2026143571000019.tif175169 Table 3: Full fit parameters for fully iodized peptoids with increasing length TIFF2026143571000020.tif58169 Example 1

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

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

[0067] SAXS allows for the determination of whether these peptoids self-assemble into nanostructures or, instead, exist as single molecules in aqueous solutions. [33-36] Furthermore, detailed theoretical modeling enables accurate estimation of molecular weight and shape, as well as estimation of the overall physical structure of the peptoid aggregates. 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 scattering vector coefficient, q = 4πsin(θ / 2) / λ, where λ is the wavelength of the X-ray and θ is the scattering angle (see Figure 3). 1 / q has the length dimension, and the quantity represents a kind of "measurement stick," noting that at low q larger structures are probed, while at high q SAXS is more sensitive to local structures.

[0068] For the decamers (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 decamers (see Figures 3A and 3B). The latter showed a typical polymer-like scattering pattern for random (Gaussian) chains, but the elevation at low q revealed a larger structure or a small portion of aggregates. The elevated portion indicates plate-like fibers ~q -2 According to the power law, it is usually ~q -4 There are no large aggregates that follow a power law. Fit analysis of these data using a model with a combination of free chains and rectangular fibers yielded a free chain radius of gyration (Rg) of 7–9 Å and a small mole fraction of only 0.001–0.0005% for fibrous sheets (see Supporting Information Table 2 for a complete list of fit parameters).

[0069] The scattering of 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 above fit model. 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 in which cylinders representing folded / helical units are assembled 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 critical aggregation concentrations (CACs) for self-assembling structures, showing CAC values ​​of 2.3 mg / mL and 0.5 mg / mL for fully brominated and fully iodized peptoids (compounds 22 and 23, respectively) (see Figure 17). The low CAC value of compound 23 may explain the loss of antimicrobial activity observed for the fully iodized decamer and dodecamer, as more peptoids are "bound" to the bundle, resulting in less availability in (presumably) active form as monomers (see Table 1).

[0070] In the case of the fully brominated compound 22, the CAC was found to be higher than the MIC value, and therefore, a significant fraction of free peptoid chains capable of interacting with bacteria still exists and does not affect their activity.

[0071] For fully iodized compound 23, the CAC was found to be much lower, most likely to dramatically reduce the availability of free monomeric peptoids, which explains the decreased antimicrobial activity of this compound. As discussed at the beginning, a similar trend was observed by Chu-Kung A. and collaborators. They concluded that a CAC close to the MIC of the free chain in their peptide system leads to a lack of antimicrobial activity in the same way we observed for compound 23.

[29] Example 2

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

[0073] To further determine whether this explains the low CAC values ​​observed from the decamer (compound 23) in the MIC data, we investigated the hexamers, octamers, and dodecamers of the fully iodized peptoid (compounds 5, 14, 23, and 32, respectively). The results are shown in Figure 3 (see Table 3 for fit parameters). From the fit analysis, a CAC of 2.8 mg / ml was observed for the fully iodized hexamer compound 5, 1.4 mg / ml for the octamer compound 14, and 0.4 mg / ml for the dodecamer compound 32.

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

[29] Thus, the decrease in activity observed for the decamers and dodecamers appears to be related to their increased hydrophobicity, suggesting that there is a threshold for staying internal rather than the self-assembly property itself. However, further research is needed on the hydrophobicity and self-assembly consequences of peptoid activity and toxicity 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 antimicrobial efficacy of known peptoids, we synthesized two small libraries of chlorinated and brominated analogs of a well-studied peptoid (peptoid 1) (these halogenated analogs showed generally higher potency compared to the fluorinated analog, while the iodine analog raised concerns regarding aggregation and loss of activity). Both halogen atoms were introduced via Nspe units at the 4-position of the phenyl ring. The level of substitution varied between complete substitution (all phenyl rings have a halogen atom) and "half" substitution (every other phenyl ring has a halogen atom). This strategy resulted in six chloro- and six bromo-modified versions of peptoid 1, as depicted in Figure 4.

[0077] A library of 12 compounds (compounds 37–48) was tested against the same panel of bacterial strains as the first generation of peptoids. However, none of the modifications resulted in increased potency; most caused loss of activity (see Table 4 below). Judging from the high retention times on long HPLC, this can be explained by the fact that critical hydrophobic levels were reached, which caused aggregation and loss of activity similar to that observed with compounds 23 and 32 (in particular, the highest activity was observed for compounds with lower retention times). Interestingly, compounds 38 and 40–42 have the same number of chlorine atoms, but their hydrophobicity differs slightly. This effect was even more pronounced for the brominated derivatives (compounds 44 and 46–48). This suggests that a uniform distribution of halogen atoms across the peptoid chain results in higher hydrophobicity compared to assigning chlorine or bromine atoms to terminal or central locations in the peptoid sequence. Table 4: MIC (μg / mL) of chlorinated and brominated analogs of peptoid 1 TIFF2026143571000021.tif102169 Example 3

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

[0079] As can be seen from the increased retention times, hydrophobicity plateaued during the introduction of halogens into the sequence of peptoid, peptoid 1 (see Table 4). Therefore, we investigated the effect of shortening the length of peptoid 1 from 12 to 6 residues (cutting its length in half). For this purpose, small libraries of four analogues were synthesized at 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, but bromination had a more pronounced effect on hydrophobicity than chlorination, similar to that shown by iodine-containing peptoids. Therefore, three brominated short peptoid analogues 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 obtained data are shown in Table 5 below, where the new dataset is compared with the original peptoid (peptoid 1) data. Table 5: MIC (μg / mL) and IC50 (μg / mL) of short brominated peptoids and peptoid 1 analogs in HaCaT cell lines. TIFF2026143571000022.tif75169

[0080] Compound 49 has only one terminal bromine atom, and 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, Pep1-6mer, by 16 to 32 times against both Staphylococcus aureus and Staphylococcus epidermidis. The incorporation of two additional bromine substituents (totaling four) did not have a significant effect on the activity. On the other hand, the addition of one terminal halogen atom was already sufficient to give a several-fold increase in antibacterial activity. In contrast to previous data (introduction of halogens did not improve activity against Gram-negative bacteria), in this case, the addition of two bromine atoms provided sufficient hydrophobicity to obtain an MIC against Pseudomonas aeruginosa close to the activity of the original peptoid (Peptoid 1), and the increase in activity against Escherichia coli reached 32 times compared to Pep1-6mer.

[0081] Since halogen uptake was found to improve the activity of inactive peptoids, the cytotoxicity profiles of the resulting compounds were investigated. Peptoid 1, Pep1-6-mer, and three brominated analogs were tested for 1 hour against HaCaT cell lines. Results were obtained using MTS / PMS assays (see Figure 5 and Table 3).

[0082] A clear trend was observed between the number of halogen atoms and the corresponding increase in cytotoxicity. However, compound 50 exhibited the same antimicrobial activity profile as peptoid 1, but with lower cytotoxicity, having an IC50 of 35.0 μg / mL compared to 146.9 μg / mL for the latter. Compounds 50 and 51 showed similar activity and hydrophobic profiles, but the first result indicates reduced cytotoxicity of the brominated analog when compared to peptoid 1. V. Conclusion

[0083] The aforementioned examples demonstrate the effects of fluorine, chlorine, bromine, and iodine substitution on the antimicrobial activity of peptoids. Firstly, the inactive form (NLys-Npm) n Using peptoid scaffolds, fluorination showed no significant effect, but the incorporation of chlorine or bromine was shown to provide improved antimicrobial activity against Gram-positive bacteria. The introduction of iodine into 6- and 8-mer analogs dramatically increased activity, but resulted in loss of activity due to aggregation in 10- and 12-mers. Attempts to improve the antimicrobial efficacy of peptoid 1 by incorporating chlorine or bromine atoms via Nspe units resulted in an overall loss of activity. While we do not wish to be bound by theory, this suggests that a hydrophobic limit has been reached. However, bromination of shorter, inactive 6-mer analogs of peptoid 1 yielded the same activity as 12-mer peptoid 1 against several bacteria, while simultaneously significantly improving its cytotoxic profile.

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

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

[0086] The halogenated compositions described herein may also be alkylated, preferably having terminal alkylation. Here, alkylation (and particularly terminal alkylation) with a C10 or C13 tail is particularly preferred. Such terminal alkylation has been found to dramatically enhance the antimicrobial activity of peptoids, and in some cases, to give 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 following formula. TIFF2026143571000023.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, wherein the one and two N-substituted glycine residues have N-substituteds independently selected from the native 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, and the N-substituents are independently selected from the group consisting of native α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of A, B, X, Y, and Z contains a halogen-containing moiety. The alkyl substituents are preferably about C4 to about C 20 Selected from linear, branched, and cyclic alkyl moieties, n preferably has a numerical value in the range of 1 to 3. Preferably, at least one of the X, Y, and Z residues is N Lys The N-substituted residue is chiral, and at least one of the N-substituted residues 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, where the alkyl substituent is C6 to about C6. 18 Selected from the group consisting of linear alkyl moieties, where B is NH2 and n is 1 or 2. In some embodiments, A is a terminal N-alkyl-substituted glycine residue, where the alkyl substituent is approximately C6 to approximately C6. 18 Selected from the linear alkyl moiety of, where B is N Lys This is a residue, where n is 1. In some embodiments, the compound may be a hexamer or a dodecamer.

[0088] In the poly-N-substituted glycine described above, the halogen-containing portion may be a halogen-substituted aryl portion, such as a chloro-substituted aryl portion, a bromo-substituted aryl portion, or an iodine-substituted aryl portion. In one embodiment, each mer may contain a halogen-substituted aryl portion, while in another embodiment, a portion of the mer may contain a halogen-substituted aryl portion, and a portion of the mer in the hexamer may contain a halogen-free aryl portion. In yet another embodiment, exactly one of the mers contains a halogen-substituted aryl portion. In some embodiments of the poly-N-substituted glycine described above, at least two of A, B, X, Y, and Z contain halogen-containing portions, while in other embodiments, all of A, B, X, Y, and Z contain halogen-containing portions. The poly-N-substituted glycine described above may include halogen substitution with any halogen, but substitution with chlorine, bromine, and / or iodine is preferred, and parahalogenation on the aryl portions on these poly-N-substituted glycines is particularly preferred.

[0089] In some embodiments, poly-N-substituted glycines may be compounds derived from materials selected from the group consisting of the compounds in Figure 1 and Figure 13 by substituting at least one hydrogen atom in at least one aryl moiety with at least one halogen atom, and more preferably by substituting at least one para-hydrogen atom in at least one aryl moiety with at least one halogen atom. In some embodiments, the compounds are derived from materials selected from the group consisting of the compounds in Figure 1 and Figure 13 by substituting one hydrogen atom in each of its aryl moieties with at least one halogen atom. In the embodiments described above, 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 one first and second distinct halogen selected from the group consisting of chlorine, bromine, and iodine. Particularly preferred embodiments of these poly-N-substituted glycines include the following compounds (or pharmaceutically acceptable salts thereof): TIFF2026143571000024.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, preferably at least two halogens, and optionally at least four halogens, selected from the group consisting of chlorine, bromine, and iodine. For example, the poly-N-substituted glycine compound may contain at least two bromine atoms or at least two chlorine atoms, or at least four bromine atoms or at least four chlorine atoms. Preferably, the poly-N-substituted glycine compound contains at least one parahalide aryl group, more preferably at least two parahalide aryl groups, and optionally at least four parahalide aryl groups. In a particularly preferred embodiment, the poly-N-substituted glycine compound contains a carboxamide-terminated group. Such compounds can be produced via linkamide resins.

[0091] The peptoids described herein may be incorporated into a variety of pharmaceutical compositions that can be used for a variety of purposes, including antimicrobial, antifungal, and possibly antiviral and antiparasitic compositions. Pharmaceutical compositions used in the systems and methods disclosed herein may utilize one or more active ingredients that can be dissolved, suspended, or disposed of in a variety of media. Such media may include, for example, a variety of liquids, solids, or multistate media such as emulsions, gels, or creams. Such media may be hydrophobic or may include liquid media that contain one or more triglycerides or oils. Examples of such media include, but are not limited to, vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, synthetic triglycerides, modified triglycerides, fractionated triglycerides, and mixtures thereof.The triglycerides used in these pharmaceutical compositions include: almond oil; babassu oil; borage oil; blackcurrant seed oil; black seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; peanut oil; mustard oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed oil and castor oil; partially hydrogenated soybean oil; glyceryl tricaprylate; 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. This may include selections from a group consisting of the following: The use of coconut oil is particularly preferable.

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

[0093] The pharmaceutical compositions disclosed herein can be applied in various forms. For example, these compositions can be applied orally, transdermally, transmucosally, intravenously, or by injection, or via cell-based drug delivery systems. Furthermore, these compositions can be applied in single-dose, multi-dose, or controlled-release forms.

[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 generally water-soluble) containing self-organizing peptoids within the micelles.

[0095] Various counterions may be used to form pharmaceutically acceptable salts of the materials disclosed herein. Those skilled in the art will understand that the specific choice of counterion may be determined by a variety of considerations. However, in some applications, the use of sodium salts and hydrochloride salts may be preferred. Generally, self-assembled peptoids are first dissolved in the absence of divalent counterions such as manganese, magnesium, and calcium.

[0096] In some embodiments, the compositions described herein may be formulated as mixtures of different peptoid compounds. For example, in some embodiments, a mixture of two or more halogenated peptoids of the types disclosed herein may be formed. In other embodiments, a mixture of one or more halogenated peptoids described herein may be formed together with one or more non-halogenated peptoids, for example, the peptoid 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 whole. It should also be noted that halogenated analogs to any of the peptoids disclosed in the '632 patent may be manufactured according to the teachings herein.

[0097] Various cyclic peptoids can be produced according to the teachings herein. These include, but are not limited to, halogenated analogs of cyclic peptoids disclosed in U.S. Patents 9,938,321 (Kirshenbaum et al.), 9,315,548 (Kirshenbaum et al.), and 8,828,413 (Kirshenbaum et al.), all of which are incorporated herein by reference in their entirety. These halogenated analogs may be characterized by halogen substitution with one or more halogens on one or more ring structures, preferably including bromo-substituted or chloro-substituted analogs.

[0098] The compositions and methodologies disclosed herein may be used in the treatment of various diseases caused by various pathogens. These treatments may utilize various other pharmaceutically active or effective substances, such as lung surfactants, collectins, peptides, peptoids, peptide mimes, aminoglycoside antibiotics, or vaccines. Pathogens treatable with these therapies may include viruses (including, but not limited to, SARS-CoV-2), bacteria (including Gram-positive and Gram-negative bacteria), fungi, and parasites.

[0099] Diseases of various terms can be treated with the compositions and methodologies disclosed herein. Examples of such diseases in fungal taxonomy include, but are not limited to, aspergillosis; candidiasis; mucormycosis; histoplasmosis; blastomycosis; coccidioidomycosis; and paracoccidioidomycosis. Examples of diseases affecting bacteriology include, but are not limited to, brucellosis; Campylobacter infection; cat scratch disease; chlamydia infection; cholera; Escherichia coli infection; gonorrhea; Klebsiella, Enterobacter, and Serratia infections; Legionella infection; meningococcal infection; pertussis; plague; Mycobacterium tuberculosis infection; Pseudomonas infection; Salmonella infection; bacterial dysentery; typhoid fever; and Mycobacterium tularensis; splenic debridement; diphtheria; enterococcal infection; eridiperotricosis; listeriosis; nocardiosis; pneumococcal infection; staphylococcal infection; streptococcal infection; spirochete infections such as Borrelia burgdorferi, Begel, Franbezia, and Pinta; leptospirosis; Lyme disease; rat-bite fever; relapsing fever; syphilis; actinomycosis; Bacteroides; botulism; Clostridium infection; and tetanus. Examples of diseases of viral origin include, for example, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Coronavirus Infection (COVID-19); Enterovirus Infections, Borna Virus Infections; Herpesvirus Infections; Cytomegaloviruses, 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; Herpes Zoster; and Yellow Fever; and Infections caused by enveloped RNA viruses, including HIV-1 (including, for example, those caused by α-coronaviruses and β-coronaviruses, specifically those caused by SARS-CoV-2, but not limited to these). Parasitic infections include those involving Toxoplasma gondii and Trypanosoma cruzi.

[0100] The above description of the present invention is illustrative and not intended to limit it. Therefore, it is clear that various additions, substitutions, and modifications can be made to the above embodiments without departing from the scope of the invention. Accordingly, the scope of the invention should be interpreted with reference to the appended claims. For convenience, some features of the claimed invention may be described separately in specific 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 disclosure. As an example, rather than an limitation, the limitations of two or more dependent claims can be combined with each other without departing from the scope of the disclosure.

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Claims

1. formula A poly-N-substituted glycine compound having or a pharmaceutically acceptable salt thereof, wherein, A is a terminal N-alkyl-substituted glycine residue, n is an integer, B is NH 2 , selected from the group consisting of one and two N-substituted glycine residues, wherein the one and two N-substituted glycine residues have N-substituteds independently selected from the natural α-amino acid side chain moiety, its isomers and carbon homologs, A poly-N-substituted glycine compound or a pharmaceutically acceptable salt thereof, wherein X, Y, and Z are independently selected from the group consisting of N-substituted glycine residues, the N-substituted member is independently selected from the group consisting of native α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, and at least one of A, B, X, Y, and Z contains a halogen-containing moiety.

2. The alkyl substituent is approximately C 4 ~About C 20 The compound according to claim 1, selected from the linear, branched, and cyclic alkyl moieties.

3. The compound according to 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 The compound according to claim 1, wherein at least one of the N-substituted groups is chiral.

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

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

7. A is a terminal N-alkyl-substituted glycine residue, and the alkyl substituent is C 6 ~About C 18 Selected from the group consisting of linear alkyl moieties, where B is NH 2 The compound according to claim 1, wherein n is 1 or 2.

8. A is a terminal N-alkyl substituted glycine residue, wherein said alkyl substituent is about C 6 to about C 18 linear alkyl moiety, B is N Lys residue, and n is 1. The compound according to claim 1.

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

10. The compound according to claim 1, wherein the compound is a dodecamer.

11. The compound according to claims 1 to 10, wherein the halogen-containing portion contains a halogen-substituted aryl portion.

12. The compound according to claims 1 to 10, wherein the halogen-containing portion contains a chlorosubstituted aryl portion.

13. The compound according to claims 1 to 10, wherein the halogen-containing portion contains a bromosubstituted aryl portion.

14. The compound according to claims 1 to 10, wherein the halogen-containing portion contains an iodine-substituted aryl portion.

15. The compound according to claim 9, wherein each of the hexamers contains a halogen-substituted aryl moiety.

16. The compound according to claim 9, wherein some of the mers in the hexamer contain a halogen-substituted aryl moiety, and some of the mers in the hexamer contain a halogen-free aryl moiety.

17. The compound according to claim 9, wherein exactly one of the hexamers contains a halogen-substituted aryl moiety.

18. The compound according to claim 10, wherein each of the hexamers contains a halogen-substituted aryl moiety.

19. The compound according to claim 10, wherein some of the mers in the hexamer include a halogen-substituted aryl moiety, and some of the mers in the hexamer include a halogen-free aryl moiety.

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

21. The compound according to claim 1, wherein at least two of A, B, X, Y, and Z contain halogen-containing moieties.

22. The compound according to claim 1, wherein A, B, X, Y, and Z all contain a halogen-containing portion.

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

24. A pharmaceutically acceptable salt of the compound according to claims 1 to 23.

25. formula A poly-N-alkyl-substituted glycine compound, or a pharmaceutically acceptable salt thereof, wherein, B is NH 2 and selected from X'; N R X, Y, Z, and X' are independently selected from N-substituted glycine residues containing N- substituents, the N-substituted of the N-substituted glycine residue being independently selected from the native α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, with at least one of the N-substituted atoms containing a halogen atom; n is an integer; and R is the same as N R The N-alkyl substituent of the glycine residue, and the substituent is approximately C 4 ~About C 20 A poly-N-alkyl-substituted glycine compound or a pharmaceutically acceptable salt thereof, selected from the linear, branched, and cyclic alkyl moieties of the glycine compound.

26. n is 2 and B is NH 2 The compound according to claim 25.

27. The compound according to claim 25, wherein n is 1 and B is X'.

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

29. The aforementioned N-alkyl substituent is approximately C 6 ~About C 18 The compound according to claim 28, selected from the linear, branched, and cyclic alkyl moieties.

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

31. formula The compound according to claim 30.

32. The alkyl substituent is approximately C 4 ~About C 20 The compound according to claim 25, selected from the linear, branched, and cyclic alkyl moieties.

33. The compound according to 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 The compound according to claim 25, wherein at least one of the N-substituted groups is chiral.

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

36. The compound according to claim 25, wherein Y and Z are proline residues.

37. A is a terminal N-alkyl-substituted glycine residue, and the alkyl substituent is C 6 From approximately C 18 Selected from the group consisting of linear alkyl moieties, where B is NH 2 The compound according to claim 25, wherein n is 1 or 2.

38. N R The terminal N-alkyl-substituted glycine residue is approximately C 6 ~About C 18 Selected from the linear alkyl moiety, where B is N Lys The compound according to claim 25, wherein n is a residue and n is 1.

39. The compound according to claim 25, wherein the compound is a hexamer.

40. The compound according to claim 25, wherein the compound is a dodecamer.

41. The compound according to claims 25 to 40, wherein the halogen-containing portion contains a halogen-substituted aryl portion.

42. The compound according to claims 25 to 40, wherein the halogen-containing portion contains a chlorosubstituted aryl portion.

43. The compound according to claims 25 to 40, wherein the halogen-containing portion contains a bromosubstituted aryl portion.

44. The compound according to claims 25 to 40, wherein the halogen-containing portion contains an iodine-substituted aryl portion.

45. The compound according to claim 39, wherein each of the hexamers contains a halogen-substituted aryl moiety.

46. The compound according to claim 39, wherein some of the mers in the hexamer contain a halogen-substituted aryl moiety, and some of the mers in the hexamer contain a halogen-free aryl moiety.

47. The compound according to claim 39, wherein exactly one of the hexamers contains a halogen-substituted aryl moiety.

48. The compound according to claim 40, wherein each of the hexamers contains a halogen-substituted aryl moiety.

49. The compound according to claim 40, wherein some of the mers in the hexamer contain a halogen-substituted aryl moiety, and some of the mers in the hexamer contain a halogen-free aryl moiety.

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

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

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

53. The compound according to claim 25, wherein the compound is an antimicrobial compound.

54. A pharmaceutically acceptable salt of the compound according to claims 25 to 53.

55. A poly-N-substituted glycine compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises an N-terminal N-alkyl substituted glycine residue, and the alkyl substituent is about C 4 to about C 20 selected from linear, branched and cyclic alkyl moieties; the C-terminus is selected from NH 2 , 1 and 2 N-substituted glycine residues, wherein the N-substituents are independently selected from α-amino acid side chain moieties and carbon homologs thereof; and each of 2 to about 15 monomer residues between the N-terminus and the C-terminus is independently selected from proline residues and N-substituted glycine residues, wherein the N-substituents are independently selected from natural α-amino acid side chain moieties, isomers thereof and carbon homologs thereof, at least one of said monomer residues is N Lys , at least one of said N-substituents is chiral, and said monomer residues are selected to provide an aperiodic sequence of monomer residues in said compound; and at least one of said residues contains at least one halogen, the poly-N-substituted glycine compound or a pharmaceutically acceptable salt thereof.

56. The N-terminus is an N-alkyl-substituted glycine residue, and the alkyl substituent is approximately C 6 ~About C 18 The compound according to claim 55, selected from the linear alkyl portion.

57. The compound according to claim 56, wherein the monomer residue comprises 2 to 5 (X-Y-Z) aperiodic trimers.

58. The compound according to claim 57, wherein at least one X, Y, and Z in each of the trimers is selected to interrupt the triple periodicity.

59. The compound according to claim 57, wherein the monomer residue comprises at least two discontinuous repeat trimers, with at least one residue between them.

60. At least one X in at least one of the trimers is N Lys The compound according to claim 59, wherein the residue is a proline residue, and at least one of Y and Z in at least one of the trimers is a proline residue.

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

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

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

64. The compound according to claim 55, wherein some of the residues include at least one halogen-substituted aryl moiety, and some of the residues include at least one non-halogenated aryl moiety.

65. The compound according to claims 62 to 64, wherein the halogen-substituted aryl portion is para-substituted.

66. The compound according to claims 62 to 64, wherein the halogen-substituted aryl portion is perhalogenated.

67. A pharmaceutically acceptable salt of the compound according to claims 55 to 66.

68. Compounds derived from a material selected from the group consisting of the compound in Figure 1 and the compound in Figure 13, by substituting at least one hydrogen atom in at least one aryl moiety with at least one halogen atom.

69. The compound according to claim 68, which is derived from a material selected from the group consisting of the compound of Figure 1 and the compound of Figure 13, by substituting at least one parahydrogen atom in at least one aryl moiety with at least one halogen atom.

70. The compound according to claim 68, which is derived from a material selected from the group consisting of the compound in Figure 1 and the compound in Figure 13 by substituting one hydrogen atom in each aryl portion with at least one halogen atom.

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

72. The compound according to claims 68 to 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 aforementioned compound . The compound according to claim 68.

74. The aforementioned compound The compound according to claim 68.

75. The aforementioned compound The compound according to claim 68.

76. A pharmaceutically acceptable salt of the compounds of claims 68 to 75.

77. A method for treating or inhibiting a disease, comprising administering to an individual having or at risk of developing the disease a certain amount of at least one poly-N-alkyl substituted glycine or a pharmaceutically acceptable salt thereof, wherein the amount of the poly-N-alkyl substituted glycine is effective in treating or inhibiting the disease, and the poly-N-alkyl substituted glycine compound has the following formula During the ceremony, B is NH 2 and selected from X'; N R X, Y, Z, and X' are independently selected from N-substituted glycine residues containing N- substituents, the N-substituted of the N-substituted glycine residue being independently selected from the native α-amino acid side chain moieties, their isomers and carbon homologs, and proline residues, with at least one of the N-substituted atoms containing a halogen atom; n is an integer; and R is the same as N R The N-alkyl substituent of the glycine residue, and the substituent is approximately C 4 ~About C 20 A method for treating or inhibiting a disease, selected from linear, branched, and cyclic alkyl moieties.

78. n is 2 and B is NH 2 The method according to claim 77.

79. The method according to claim 77, wherein n is 1 and B is X'.

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

81. The aforementioned N-alkyl substituent is approximately C 6 ~About C 18 The method according to claim 80, wherein the linear, branched, and cyclic alkyl moieties are selected from the linear, branched, and cyclic alkyl moieties.

82. X and X' are N Lys The method according to claim 81, wherein the residue is a residue.

83. formula The method according to claim 82.

84. The alkyl substituent is approximately C 4 ~About C 20 The method according to claim 77, wherein the linear, branched, and cyclic alkyl moieties are selected from the linear, branched, and cyclic alkyl moieties of the product.

85. The method according to 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 The method according to claim 77, wherein at least one of the N-substituted atoms is chiral.

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

88. The method according to claim 77, wherein Y and Z are proline residues.

89. A is a terminal N-alkyl-substituted glycine residue, and the alkyl substituent is C 6 From approximately C 18 Selected from the group consisting of linear alkyl moieties, where B is NH 2 The method according to claim 77, wherein n is 1 or 2.

90. N R The terminal N-alkyl-substituted glycine residue is approximately C 6 ~About C 18 Selected from the linear alkyl moiety, where B is N Lys The method according to claim 77, wherein the residue is n is 1.

91. The method according to claim 77, wherein the compound is a hexamer.

92. The method according to claim 77, wherein the compound is a dodecamer.

93. The method according to claims 77 to 92, wherein the halogen-containing portion contains a halogen-substituted aryl portion.

94. The method according to claims 77 to 92, wherein the halogen-containing portion contains a chlorosubstituted aryl portion.

95. The method according to claims 77 to 92, wherein the halogen-containing portion contains a bromosubstituted aryl portion.

96. The method according to claims 77 to 92, wherein the halogen-containing portion contains an iodine-substituted aryl portion.

97. The method according to claim 91, wherein each of the hexamers contains a halogen-substituted aryl moiety.

98. The method according to claim 91, wherein some of the mers in the hexamer contain a halogen-substituted aryl moiety, and some of the mers in the hexamer contain a halogen-free aryl moiety.

99. The method according to claim 91, wherein exactly one of the hexamers contains a halogen-substituted aryl moiety.

100. The method according to claim 92, wherein each of the hexamers contains a halogen-substituted aryl portion.

101. The method according to claim 92, wherein some of the mers in the hexamer contain a halogen-substituted aryl moiety, and some of the mers in the hexamer contain a halogen-free aryl moiety.

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

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

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

105. The method according to claim 77, wherein the compound is an antimicrobial compound.

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

107. The method according to claim 77, wherein the disease is caused by a coronavirus.

108. The method according to 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 according to claim 107, wherein the disease is COVID-19.

110. A method for treating or inhibiting a disease, comprising administering to an individual having or at risk of developing the disease a certain amount of at least one poly-N-alkyl-substituted glycine or a pharmaceutically acceptable salt thereof, wherein the amount of the poly-N-alkyl-substituted glycine is effective in treating or inhibiting the disease, and the 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 substituting at least one hydrogen atom in at least one aryl portion thereof with at least one halogen atom, or a pharmaceutically acceptable salt thereof.

111. The method according to claim 110, wherein the compound is derived from a material selected from the group consisting of the compound of Figure 1 and the compound of Figure 13, by substituting at least one parahydrogen atom in at least one aryl portion with at least one halogen atom.

112. The method according to claim 110, wherein the compound is derived from a material selected from the group consisting of the compound of Figure 1 and the compound of Figure 13, by substituting one hydrogen atom in each aryl portion with at least one halogen atom.

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

114. The method according to 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 aforementioned compound, The method according to claim 110.

116. The aforementioned compound, The method according to claim 110.

117. The aforementioned compound, The method according to claim 110.

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

119. The method according to claim 110, wherein the disease is caused by a coronavirus.

120. The method according to 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 according to 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 the disease a certain amount of a poly-N-alkyl-substituted glycine or a pharmaceutically acceptable salt thereof, wherein the amount of the poly-N-alkyl-substituted glycine is effective in treating or inhibiting the disease, and the poly-N-alkyl-substituted glycine compound comprises an N-terminal N-alkyl-substituted glycine residue, and the alkyl substituent is approximately C 4 ~About C 20 Selected from linear, branched, and cyclic alkyl moieties, the C-terminus is NH 2 , selected from 1 and 2 N-substituted glycine residues, the N-substituents are independently selected from the α-amino acid side chain moiety and its carbon homolog, and each of the 2 to about 15 monomer residues between the N-terminus and C-terminus is independently selected from proline residues and N-substituted glycine residues, the N-substituents are independently selected from the native α-amino acid side chain moiety, its isomers and their carbon homologs, and at least one of the monomer residues is N Lys A method for treating or inhibiting a disease, wherein at least one of the N-substituents is chiral, the monomer residues are selected to provide the compound with a non-periodic sequence of monomer residues, and at least one of the residues contains at least one halogen.

123. The N-terminus is an N-alkyl-substituted glycine residue, and the alkyl substituent is approximately C 6 ~About C 18 The method according to claim 122, wherein the linear alkyl portion is selected from the linear alkyl portion.

124. The method according to claim 123, wherein the monomer residue comprises 2 to 5 (X-Y-Z) aperiodic trimers.

125. The method according to claim 124, wherein at least one X, Y, and Z in each of the trimers is selected to interrupt the triple periodicity.

126. The method according to claim 124, wherein the monomer residue comprises at least two discontinuous repeat trimers and has at least one residue between them.

127. At least one X in at least one of the trimers is N Lys The method according to claim 126, wherein the residue is a proline residue, and at least one of Y and Z in at least one of the trimers is a proline residue.

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

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

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

131. The method according to claim 122, wherein some of the residues include at least one halogen-substituted aryl moiety, and some of the residues include at least one non-halogenated substituted aryl moiety.

132. The method according to claims 129 to 131, wherein the halogen-substituted aryl portion is para-substituted.

133. The method according to claims 129 to 131, wherein the halogen-substituted aryl portion is perhalogenated.

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

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

136. The method according to claim 122, wherein the disease is caused by a coronavirus.

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

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

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

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

145. The method according to claim 140, wherein the poly-N-substituted glycine compound contains at least one parahalogenated aryl group.

146. The method according to claim 139, wherein the poly-N-substituted glycine compound contains at least two parahalogenated aryl groups.

147. The method according to claim 139, wherein the poly-N-substituted glycine compound contains at least four parahalogenated aryl groups.

148. The method according to claim 140, wherein the poly-N-substituted glycine compound contains at least one para-chlorinated aryl group.

149. The method according to claim 139, wherein the poly-N-substituted glycine compound contains at least two para-chlorinated aryl groups.

150. The method according to claim 139, wherein the poly-N-substituted glycine compound contains at least four para-chlorinated aryl groups.

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

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

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

154. The method according to claim 139, wherein the poly-N-substituted glycine compound contains a carboxamide terminal group.

155. The method according to claim 139, wherein the poly-N-substituted glycine compound is produced via a linkamide resin.

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