Native glycosylation and binding of the antidepressant paroxetine in a low-resolution crystal structure of human myeloperoxidase.

Human myeloperoxidase (MPO) utilizes hydrogen peroxide to oxidize organic compounds and as such plays an essential role in cell-component synthesis, in metabolic and elimination pathways, and in the front-line defence against pathogens. Moreover, MPO is increasingly being reported to play a role in inflammation. The enzymatic activity of MPO has also been shown to depend on its glycosylation. Mammalian MPO crystal structures deposited in the Protein Data Bank (PDB) present only a partial identification of their glycosylation. Here, a newly obtained crystal structure of MPO containing four disulfide-linked dimers and showing an elaborate collection of glycans is reported. These are compared with the glycans identified in proteomics studies and from 18 human MPO structures available in the PDB. The crystal structure also contains bound paroxetine, a blocker of serotonin reuptake that has previously been identified as an irreversible inhibitor of MPO, in the presence of thiocyanate, a physiological substrate of MPO.

Anti-inflammatory, antioxidant effects, and bioaccessibility of Tigzirt propolis.

This work aims to assess the anti-inflammatory effects of Tigzirt propolis native to Algeria. We divided 48 male Wistar rats into 8 groups. We orally administered ethyl acetate extract of propolis (EAP), pure polyphenols compounds, or diclofenac 5 days before induction of inflammation by of carrageenan (100 µg/ml, i.p.). We determined the development of paw edema, biological parameters, myeloperoxidase activity, TNF-α, and prostaglandin E2 and measured the oxidative status parameters, as well. Finally, we analyzed the absorption and bioaccessibility of propolis in rats' plasma using GC-MS after orally dosing rats (250 mg/kg). The pretreatment by 200 and 250 mg/kg of propolis significantly reduced the edema rates after the third hour. Propolis can restore the disruption of homeostasis as well as markers of inflammation induced by carrageenan in Wistar rats, and an increase of the enzymatic activities. Furthermore, the inflammation was better resolved in rats that received propolis than in those treated with pure polyphenols. PRACTICAL APPLICATIONS: Propolis is a natural mixture that bees produce by mixing gathered resin and gums to bee saliva and wax. Our research investigated the effect of Tigzirt propolis on the inhibition of biomarkers of inflammation and the development of paw edema. Propolis extract helped to reduce PGE2, TNF-α, myeloperoxidase, and malondialdehyde levels and increase the total antioxidant levels in plasma. Our findings emphasized the use of phenolic extract of propolis in industries such as nutraceuticals for the prevention of inflammatory diseases. It can also protect the body against damage under oxidative stress.

On the Clinical Pharmacology of Reactive Oxygen Species.

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.

A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019).

INTRODUCTION: Myeloperoxidase (MPO) is an immune enzyme found in neutrophils and macrophages. It produces the highly oxidative compound HOCl from H2O2 and Cl- ions inside the phagosome of the neutrophil. Leakage of the enzyme outside the cell causes oxidative damages for the biomolecules promoting many inflammatory diseases such as atherosclerosis. Thus, there is a real interest to develop potent inhibitors of MPO as non-steroidal anti-inflammatory agents. This review highlights the several published MPO inhibitors, their activity, and the challenges met during the development of these compounds. AREAS COVERED: This article covers the patent literature published on MPO inhibitors from 2013 to 2019, as well as the potential use of these compounds as therapeutics for inflammatory syndromes, especially that plays an important role in the initiation and progression of atherosclerosis. EXPERT OPINION: To date, many MPO inhibitors with different structures have been studied, many of which have prominent inhibitory activities. Furthermore, the specificity of these drugs offers hope for the targeted therapy of inflammatory syndromes. Although many data have proved that MPO can contribute to several chronic inflammatory syndromes, the usefulness of MPO inhibitors in preventing and treating inflammatory disorders is still under investigation.

Chemical composition of propolis extract and its effects on epirubicin-induced hepatotoxicity in rats

ABSTRACT Propolis is a natural substance, produced by honeybees from the resin of various plants. The purpose of this study was to determine the chemical composition and evaluate the hepatoprotective effect of ethyl acetate extract of propolis from Tigzirt, against the toxicity induced by epirubicin which is a anticancer agent, and belongs to the family of antracyclines. The study included thirty male Wistar albino rats divided into five groups. The rats received the extraction of propolis or the quercetin orally for 15 days. The hepatotoxicity was promoted by injection epirubicin (i.v.) with a cumulative dose of 9 mg/kg. Several biological parameters were measured. Oxidative status was also assessed by evaluating antioxidant enzyme and histological study of some organs. Epirubicin caused oxidative stress by a significant decrease in hepatic antioxidant enzymes (gluthation peroxidase, catalase, superoxide dismutase), increased malondialdehyde and liver parameters (ASAT, ALAT, γGT, ALP) compared to the control. The histological study revealed major damage to the liver. Perturbations in this liver function, antioxidant status and damage to the liver by epirubicin have been repaired by the administration of propolis. Furthermore, epirubicin showed inflammatory effects induced by an increase in TNF-α and PGE2. Pretreatment with propolis to rats restored these inflammatory parameters. The chemical identification of extract of propolis by HPLC/UV shows the presence of polyphenolic compounds and many flavonoids. The propolis extract showed a significant reduction in oxidative damage from oxidative stress and a very important protective effect against epirubicin-induced hepatotoxicity.

The soluble curcumin derivative NDS27 inhibits superoxide anion production by neutrophils and acts as substrate and reversible inhibitor of myeloperoxidase.

A water-soluble curcumin lysinate incorporated into hydroxypropyl-ß-cyclodextrin (NDS27) has been developed and shown anti-inflammatory properties but no comparative study has been made in parallel with its parent molecule, curcumin on polymorphonuclear neutrophils (PMNs) and myeloperoxidase (MPO) involved in inflammation. The effect of NDS27, its excipients (hydroxypropyl-ß-cyclodextrin and lysine), curcumin lysinate and curcumin were compared on the release of superoxide anion by PMNs using a chemiluminescence assay and on the enzymatic activity of MPO. It was shown that curcumin and NDS27 exhibit similar inhibition activities on superoxide anion release by stimulated PMNs but also on MPO peroxidase and halogenation activities. The action mechanism of curcumin and NDS27 on the MPO activity was refined by stopped-flow and docking analyses. We demonstrate that both curcumin and NDS27 are reversible inhibitors of MPO by acting as excellent electron donors for redox intermediate Compound I (∼107 M-1 s-1) but not for Compound II (∼103 M-1 s-1) in the peroxidase cycle of the enzyme, thereby trapping the enzyme in the Compound II state. Docking calculations show that curcumin is able to enter the enzymatic pocket of MPO and bind to the heme cavity by π-stacking and formation of hydrogen bonds involving substituents from both aromatic rings. Hydroxypropyl-ß-cyclodextrin is too bulky to enter MPO channel leading to the binding site suggesting a full release of curcumin from the cyclodextrin thereby allowing its full access to the active site of MPO. In conclusion, the hydroxypropyl-ß-cyclodextrin of NDS27 enhances curcumin solubilization without affecting its antioxidant capacity and inhibitory activity on MPO.

Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents.

Group IV cytosolic phospholipase A2 (cPLA2α) plays a critical role in inflammatory processes. It produces arachidonic acid which is the main source of the pro-inflammatory eicosanoids mediators that are important in innate immune system. In some cases, these proinflammatory mediators cause damages to the host tissues and therefore promote autoimmune diseases. Consequently, development of potent inhibitors against cPLA2α could improve the therapy of inflammatory diseases. In the last two decades, intense efforts have been done to find potent cPLA2α inhibitors. Several scaffolds have been developed with the use of structure activity relationship (SAR) studies, and potent inhibitors have been obtained. The poor absorption of these compounds from intestine was the main challenge for clinical application. This review illustrates the search for cPLA2α inhibitors, their SAR studies and biological effects.

Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure.

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 µM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.

From Dynamic Combinatorial Chemistry to in Vivo Evaluation of Reversible and Irreversible Myeloperoxidase Inhibitors.

The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.

Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study.

Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 µM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).

Characterization of chemical features of potent myeloperoxidase inhibitors.

BACKGROUND: Despite its important role in the immune system, myeloperoxidase (MPO) is implicated in a wide range of inflammatory syndromes due to its oxidative product HOCl. The oxidative damages caused by MPO make it a new target for developing promising anti-inflammatory agents. In this paper, we tried to understand the mechanism of MPO inhibition in order to facilitate the drug design, to develop more accurate virtual tests and to understand the structure-activity relationship. RESULTS: Based on docking experiments, kinetic studies and in vitro tests, it is determined that a potent MPO inhibitor must possess an oxidizable group in addition to a high affinity with the active site. At last, a new hit was found in this work namely 4-(3-hydroxy-phenoxy)-butylamine (5) that has IC50 of 86 nM. CONCLUSION: Hydroxy-phenoxy alkylamine derivatives were found to be promising MPO inhibitors and they may represent an important starting point in the development of more potent MPO inhibitors.

Myeloperoxidase as a Target for the Treatment of Inflammatory Syndromes: Mechanisms and Structure Activity Relationships of Inhibitors.

Inflammation is an initial response of the body to a harmful stimuli and it is achieved by the increased movement of leukocytes (especially granulocytes) from blood into injured tissues. It is required for healing wounds and infections. Despite their indispensable role in microbial killing, the inflammation reactions may also cause diseases to a host such as hay fever, atherosclerosis, and rheumatoid arthritis. The enzymes and oxidizing species released during the inflammatory process can cause damages to the host tissues which lead to inflammatory syndromes. The role of myeloperoxidase (MPO) in the inflammatory reactions is well documented. It contributes in killing the pathogens but it is also implicated in several inflammatory syndromes such as Parkinson's disease, Alzheimer's disease and atherosclerosis. Thus, this enzyme has attracted more attention of the scientists and it has become a target for drug designing. In the last decade, several reversible and irreversible MPO inhibitors were identified as very high potent inhibitors such as fluoroalkylindole, aromatic hydroxamic acid, thioxanthine and benzoic acid hydrazide derivatives. In this review, we tried to illustrate the MPO inhibitors and highlight their structure activity relationship (SAR). In this paper we also discussed the mechanism of the inhibitory effect of the most potent compounds.

Type 2 17-ß hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis.

Low estradiol level in postmenopausal women is implicated in osteoporosis, which occurs because of the high bone resorption rate. Estrogen formation is controlled by 17-ß hydroxysteroid dehydrogenase 17-ß HSD enzymes, where 17-ß HSD type 1 contributes in the formation of estradiol, while type 2 catalyzes its catabolism. Inhibiting 17-ß HSD2 can help in increasing estradiol concentration. Several promising 17-ß HSD2 inhibitors that can act at low nanomolar range have been identified. However, there are some specific challenges associated with the application of these compounds. Our review provides an up-to-date summary of the current status and recent progress in the production of 17-ß HSD2 inhibitors as well as the future challenges in their clinical application.

Inhibition of myeloperoxidase activity by the alkaloids of Peganum harmala L. (Zygophyllaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Seeds and aerial parts of Peganum harmala L. are widely used in Algeria as anti-inflammatory remedies. Evaluation of Peganum harmala total alkaloids extracts and pure ß-carboline compounds as an anti-inflammatory treatment by the inhibition of an enzyme key of inflammatory, myeloperoxidase (MPO) and HPLC quantification of the alkaloids from the different parts of plant. MATERIALS AND METHODS: MPO inhibition was tested using taurine chloramine test. The inhibition of LDL oxidation induced by MPO was carried out. The molecular docking analysis of Peganum harmala alkaloids on MPO was performed using the Glide XP docking protocol and scoring function and the redox potential of alkaloids was determined using an Epsilon potentiostat. The concentration of harmala alkaloids was determined using HPLC analysis. RESULTS: The HPLC profiling of the active total alkaloids indicates that ß-carboline e.g. harmine, harmaline, harmane, harmol and harmalol are major components. As ß-carbolines resemble tryptamine, of which derivatives are efficient inhibitors of MPO, the harmala alkaloids were tested for their activity on this enzyme. Total alkaloids of the seeds and of the aerial parts strongly inhibited MPO at 20µg/mL (97±5% and 43±4%, respectively) whereas, at the same concentration, those of the roots showed very low inhibition (15±6%). Harmine, harmaline and harmane demonstrated a significant inhibition of MPO at IC50 of 0.26, 0.08 and 0.72µM respectively. These alkaloids exerted a similar inhibition effects on MPO-induced LDL oxidation. Molecular docking analysis of Peganum harmala alkaloids on MPO showed that all active Peganum harmala alkaloids have a high affinity on the active site of MPO (predicted free energies of binding up to -3.1kcal/mol). Measurement of redox potentials versus the normal hydrogen electrode clearly differentiated (i) the high MPO inhibitory activity of harmine, harmaline and harmane (+1014, 1014 and 1003mV, respectively); and (ii) the low activity of harmalol and harmol (+629/778 and 532/644mV, respectively). A reverse phase HPLC method has been developed to determine simultaneously five alkaloids of Peganum harmala. Seeds contained all five ß-carboline derivatives with the main active alkaloids, harmaline and harmine, being up to 3.8% and 2.9%, respectively. Up to 3.2% of harmine was determined in the roots. The four ß-carboline derivatives, harmine, harmaline, harmane and harmalol were identified in the aerial parts. The highest inhibitory effect observed in seeds and the moderate effect of aerial parts could be explained by their harmine and harmaline content. In contrast, the very weak inhibition of the root extract, despite the presence of harmine, may tentatively be explained by the high concentration of harmol which can reduce Compound II of MPO to the native form. CONCLUSION: The inhibition of MPO by Peganum harmala ß-carboline alkaloids, herein reported for the first time, may explain the anti-inflammatory effect traditionally attributed to its herbal medicine.

Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake: a possible new approach of major depressive disorders with inflammatory syndrome.

OBJECTIVES: Major depressive disorder (MDD) is accompanied with an imbalance in the immune system and cardiovascular impairments, such as atherosclerosis. Several mechanisms have been pointed out to underlie this rather unexpected association, and among them the activity of myeloperoxidase (MPO). The aim of our study was to find compounds that inhibit both MPO and serotonin transporter (SERT) for treating MDD associated with cardiovascular diseases. METHODS: SERT inhibition was assessed with measuring of [(3) H]-serotonin uptake using HEK-293 MSR cells. MPO inhibition was determined by taurine chloramine test on 3-(aminoalkyl)-5-fluoroindole derivatives and on clinically relevant antidepressants. All kinetic measurements were performed using a temperature-controlled stopped-flow apparatus (model SX-18 MV). Promising lead compounds were docked onto SERT 3D structure modelled using the LeuT structure complexed to tryptophan (PDB code 3F3A). Their toxicological profile was also assessed. KEY FINDINGS: 3-(aminoalkyl)-5-fluoroindole derivative with 5 carbons on the side chain and paroxetine showed the best activity on both MPO and SERT at the nanomolar range. Paroxetine was found to be the first irreversible MPO inhibitor at nanomolar concentrations. CONCLUSIONS: Our results put forward the first hybrid molecule (compound 25) and drug (paroxetine) that can be especially used in MDD associated with inflammatory syndrome.

Characterization and antioxidant properties of six Algerian propolis extracts: ethyl acetate extracts inhibit myeloperoxidase activity.

Because propolis contains many types of antioxidant compounds such as polyphenols and flavonoids, it can be useful in preventing oxidative damages. Ethyl acetate extracts of propolis from several Algerian regions show high activity by scavenging free radicals, preventing lipid peroxidation and inhibiting myeloperoxidase (MPO). By fractioning and assaying ethyl acetate extracts, it was observed that both polyphenols and flavonoids contribute to these activities. A correlation was observed between the polyphenol content and the MPO inhibition. However, it seems that kaempferol, a flavonoid, contributes mainly to the MPO inhibition. This molecule is in a high amount in the ethyl acetate extract and demonstrates the best efficiency towards the enzyme with an inhibiting concentration at 50% of 4 ± 2 µM.

Interplay between Halogen Bonding and Lone Pair-π Interactions: A Computational and Crystal Packing Study.

The supramolecular organization of modified thiophenes resulting from N⋅⋅⋅I halogen bonding (XB) has been studied. X-ray diffraction analyses of two polymorphs of the same supramolecular complex showed an arrangement controlled by halogen-bonded pyridyl and tetrafluoroiodobenzene rings, one case with and the other without the presence of two different lone pair (lp)⋅⋅⋅π interactions, namely O⋅⋅⋅pyridyl and I⋅⋅⋅tetrafluoroiodobenzene contacts. To shed light on the interplay between these interactions, quantum mechanical calculations were performed at the ωB97X-D/6-31+G(d,p) level on both systems in the gas phase. The longer N⋅⋅⋅I distance observed in the crystal structure without lp⋅⋅⋅π interactions was also corroborated by dispersion-corrected DFT. These results represent the first case in which a synergy between lp⋅⋅⋅π interactions and XB is observed experimentally and confirmed by calculations.

Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors.

Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.

Evaluation of new scaffolds of myeloperoxidase inhibitors by rational design combined with high-throughput virtual screening.

Myeloperoxidase (MPO) is a major player of the innate immune defense system of human neutrophils and catalyzes the production of strong oxidizing and halogenating antimicrobial products. Because of its role in pathogenesis of many (inflammatory) diseases, there is great interest in the development of efficient and specific inhibitors. Here, using the X-ray structure of MPO, high-throughput molecular docking of 1350000 compounds was performed. From this virtual screening process, 81 were tested for inhibition of the chlorination activity of MPO, finally ending up with eight inhibiting candidates of different chemical structures. These were tested for inhibiting MPO-mediated low-density lipoprotein oxidation and for interacting with the relevant redox intermediates of MPO. The best inhibitors were bis-2,2'-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol and 8-[(2-aminoethyl)amino]-3,7-dihydro-3-methyl-7-(3-phenoxypropyl)-1H-purine-2,6-dione. Both did not irreversibly inactivate the enzyme but efficiently trapped it in its compound II state. We discuss the mechanism of inactivation as well as pros and cons of the performed selection process.

Structure-based design, synthesis, and pharmacological evaluation of 3-(aminoalkyl)-5-fluoroindoles as myeloperoxidase inhibitors.

Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles.