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1.
Bioorg Med Chem Lett ; 98: 129589, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38097140

ABSTRACT

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.


Subject(s)
Peptides, Cyclic , Receptor Tyrosine Kinase-like Orphan Receptors , Adult , Humans , Cell Line, Tumor , Receptor Tyrosine Kinase-like Orphan Receptors/drug effects , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology
2.
Angew Chem Int Ed Engl ; 60(42): 22640-22645, 2021 10 11.
Article in English | MEDLINE | ID: mdl-34383389

ABSTRACT

Recent improvements in mRNA display have enabled the selection of peptides that incorporate non-natural amino acids, thus expanding the chemical diversity of macrocycles beyond what is accessible in nature. Such libraries have incorporated non-natural amino acids at the expense of natural amino acids by reassigning their codons. Here we report an alternative approach to expanded amino-acid diversity that preserves all 19 natural amino acids (no methionine) and adds 6 non-natural amino acids, resulting in the highest sequence complexity reported to date. We have applied mRNA display to this 25-letter library to select functional macrocycles that bind human STING, a protein involved in immunoregulation. The resulting STING-binding peptides include a 9-mer macrocycle with a dissociation constant (KD ) of 3.4 nM, which blocks binding of cGAMP to STING and induces STING dimerization. This approach is generalizable to expanding the amino-acid alphabet in a library beyond 25 building blocks.


Subject(s)
Membrane Proteins/metabolism , Peptides, Cyclic/metabolism , RNA, Messenger/metabolism , Amino Acid Sequence , Amino Acids/chemistry , Codon , Cyclic AMP/chemistry , Cyclic AMP/metabolism , Cyclic GMP/chemistry , Cyclic GMP/metabolism , Dimerization , Genetic Engineering , Humans , Kinetics , Membrane Proteins/chemistry , Peptide Library , Peptides, Cyclic/chemistry , RNA, Messenger/genetics
3.
Exp Cell Res ; 332(2): 267-77, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25486070

ABSTRACT

Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein.


Subject(s)
Myeloid Cell Leukemia Sequence 1 Protein/genetics , Apoptosis , Cell Line, Tumor , Cell Survival , Gene Expression , Gene Knockdown Techniques , Humans , Mitochondria/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/therapy , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA Interference , RNA, Small Interfering/genetics
4.
J Labelled Comp Radiopharm ; 57(9): 579-83, 2014 Jul.
Article in English | MEDLINE | ID: mdl-25089024

ABSTRACT

The synthesis of a 16-residue, stable isotopically labeled peptide is described for use as a LC-MS/MS (Liquid chromatography-mass spectrometry/mass spectrometry) internal standard in bioanalytical studies. This peptide serves as a single universal surrogate peptide capable of quantifying a wide variety of immunoglobulin G and Fc-fusion protein drug candidates in animal species used in pre-clinical drug development studies. An efficient synthesis approach for this peptide was developed using microwave-assisted solid phase peptide synthesis (SPPS) techniques, which included the use of a pseudoproline dipeptide derivative. The corresponding conventional room temperature SPPS was unsuccessful and gave only mixtures of truncated products. Stable-labeled leucine was incorporated as a single residue via manual coupling of commercially available Fmoc-[(13) C6 , (15) N]-l-leucine onto an 11-unit segment followed by automated microwave-assisted elaboration of the final four residues. Using this approach, the desired labeled peptide was prepared in high purity and in sufficient quantities for long-term supplies as a bioanalytical internal standard. The results strongly demonstrate the importance of utilizing both microwave-assisted peptide synthesis and pseudoproline dipeptide techniques to allow the preparation of labeled peptides with highly lipophilic and sterically hindered side-chains.


Subject(s)
Chromatography, Liquid/standards , Mass Spectrometry/standards , Peptide Fragments/chemical synthesis , Solid-Phase Synthesis Techniques/methods , Amino Acid Sequence , Carbon Radioisotopes/chemistry , Chromatography, Liquid/methods , Humans , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin G/chemistry , Mass Spectrometry/methods , Microwaves , Molecular Sequence Data , Nitrogen Isotopes/chemistry , Reference Standards
5.
Peptides ; 31(7): 1353-60, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20420872

ABSTRACT

We report the identification of potent agonists of the Glucagon-Like Peptide-1 receptor (GLP-1R) via evaluation of two positional scanning libraries and a two-dimensional focused library, synthesized in part on SynPhase Lanterns. These compounds are 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of biphenylalanine (Bip) at the two C-terminal positions. Typical activities of the most potent peptides in this class are in the picomolar range in an in vitro functional assay using human GLP-1 receptor.


Subject(s)
Peptides/chemistry , Receptors, Glucagon/agonists , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Glucagon-Like Peptide-1 Receptor , Humans , Models, Molecular , Molecular Sequence Data , Peptide Library , Peptides/metabolism , Peptides/pharmacology , Structure-Activity Relationship
6.
Peptides ; 31(5): 950-5, 2010 May.
Article in English | MEDLINE | ID: mdl-20138099

ABSTRACT

We report the identification of potent agonists of the Glucagon-Like Peptide-1 Receptor (GLP-1R). These compounds are short, 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of homohomophenylalanine (hhPhe) at the C-terminal position. Typically the functional activity of the more potent peptides in this class is in the low picomolar range in an in vitro cAMP assay, with one example demonstrating excellent in vivo activity in an ob/ob mouse model of diabetes.


Subject(s)
Aminobutyrates/chemistry , Peptides/chemistry , Receptors, Glucagon/agonists , Amino Acid Sequence , Animals , Blood Glucose/drug effects , CHO Cells , Cricetinae , Cricetulus , Glucagon-Like Peptide-1 Receptor , Hyperglycemia/blood , Hyperglycemia/drug therapy , Mice , Molecular Sequence Data , Molecular Structure , Peptides/chemical synthesis , Peptides/pharmacokinetics , Peptides/therapeutic use
7.
J Med Chem ; 52(23): 7788-99, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19702274

ABSTRACT

Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.


Subject(s)
Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Receptors, Glucagon/agonists , Amino Acid Sequence , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Glucagon-Like Peptide-1 Receptor , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Mice , Models, Molecular , Molecular Sequence Data , Oligopeptides/chemical synthesis , Oligopeptides/pharmacokinetics , Protein Conformation
8.
Bioorg Med Chem ; 15(22): 7087-97, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17869116

ABSTRACT

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, substituted at the 2-position with piperidines bearing quaternary ammonium salt side chains, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Attachment of the charged entity using an N-ethylcarbamoyloxy linker led to the discovery of the highly soluble compound 22 (D13-9001), which maintained good potency in vitro and displayed excellent activity in vivo in a rat pneumonia model of P. aeruginosa.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Outer Membrane Proteins/antagonists & inhibitors , Piperidines/pharmacology , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Quaternary Ammonium Compounds/pharmacology , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Drug Evaluation, Preclinical , Drug-Related Side Effects and Adverse Reactions , Female , Haplorhini , Infusions, Intravenous , Male , Membrane Transport Proteins , Microbial Sensitivity Tests , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Quaternary Ammonium Compounds/administration & dosage , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/chemistry , Rats , Rats, Sprague-Dawley , Solubility , Stereoisomerism
9.
Bioorg Med Chem ; 14(24): 8506-18, 2006 Dec 15.
Article in English | MEDLINE | ID: mdl-16979895

ABSTRACT

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with aromatic substituents, were synthesized by the Suzuki cross-coupling method and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. By incorporating hydrophilic substituents onto the aryl nucleus, we found a morpholine analogue that possessed improved solubility, retained activity in vitro, and displayed potentiation activity in vivo in a rat model of P. aeruginosa pneumonia.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Outer Membrane Proteins/antagonists & inhibitors , Pseudomonas aeruginosa/drug effects , Pyrimidines/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Aztreonam/chemistry , Aztreonam/pharmacology , Levofloxacin , Lung/drug effects , Lung/microbiology , Membrane Transport Proteins , Microbial Sensitivity Tests , Ofloxacin/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Rats , Rats, Sprague-Dawley
10.
Bioorg Med Chem Lett ; 16(23): 5963-7, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-16997550

ABSTRACT

A series of borinic acid picolinate esters were synthesized and screened for their minimum inhibitory concentration (MIC) against Gram-positive and -negative bacteria. Our lead compounds were then screened for anti-inflammatory activity. From these studies, we identified 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)borane (2g, AN0128) as having the best combination of anti-bacterial and anti-inflammatory activities. This compound is now in clinical development for dermatological conditions.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Boranes/chemical synthesis , Boranes/pharmacology , Boron/chemistry , Pyridines/chemical synthesis , Pyridines/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Inflammatory Agents/chemistry , Boranes/chemistry , Boron Compounds/chemistry , Cytokines/metabolism , Esters/chemistry , Humans , Leukocytes/drug effects , Leukocytes/metabolism , Molecular Structure , Pyridines/chemistry , Skin Diseases/drug therapy , Structure-Activity Relationship
11.
Bioorg Med Chem ; 14(6): 1993-2004, 2006 Mar 15.
Article in English | MEDLINE | ID: mdl-16290941

ABSTRACT

A series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives, derivatized at the 2-position with carbon-linked substituents, were synthesized and evaluated for their ability to potentiate the activity of the fluoroquinolone levofloxacin (LVFX) and the anti-pseudomonas beta-lactam aztreonam (AZT) in Pseudomonas aeruginosa. Palladium-catalyzed cross-coupling methods were applied for the incorporation of aliphatic and aromatic substituents.


Subject(s)
Bacterial Outer Membrane Proteins/antagonists & inhibitors , Carbon/chemistry , Carbon/pharmacology , Drug Resistance, Bacterial/drug effects , Models, Chemical , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Inhibitory Concentration 50 , Membrane Transport Proteins , Microbial Sensitivity Tests
12.
Recent Pat Antiinfect Drug Discov ; 1(2): 157-75, 2006 Jun.
Article in English | MEDLINE | ID: mdl-18221142

ABSTRACT

Active efflux is a widespread mechanism for bacterial resistance to antibiotics, which contributes to poor intrinsic susceptibility, cross-resistance to structurally diverse classes of drugs, or selection of other mechanisms of resistance. Thus, inhibition of efflux pumps appears to be (i) a promising strategy for restoring the activity of existing antibiotics, and (ii) a useful method to detect the presence of efflux determinants in clinical isolates. Structurally dissimilar classes of inhibitors have been patented in the last decade, some are analogs of antibiotic substrates [tetracyclines, quinolones or aminoglycosides] and others, new chemical entities [including substituted indoles, ureas, aromatic amides, piperidinecarboxylic acids, alkylamino- or alkoxyquinolines, peptidomimetics, and pyridopyrimidines]. Their spectrum of activity, in terms of antibiotics and bacteria, differ significantly. Narrow spectrum inhibitors are of prime interest as diagnostic tools, while broad spectrum inhibitors are expected for adjuvant therapies. Apart from (i) a peptidomimetic inhibitor of Mex pumps in Pseudomonas aeruginosa (MC-04,124), for which efficacy was evaluated in animal models, and (ii) a piperidinecarboxylic acid inhibitor of fluoroquinolone efflux in Gram-positive (VX-710), which was safely administered to humans, most of these products have only demonstrated their activity in vitro, so further investigations are needed to evaluate their clinical potential.


Subject(s)
Adjuvants, Pharmaceutic/pharmacology , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacteria/metabolism , Drug Resistance, Bacterial/physiology , Membrane Transport Proteins/drug effects , Adjuvants, Pharmaceutic/therapeutic use , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/classification , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Drug Resistance, Bacterial/genetics , Humans , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Patents as Topic
13.
Biochemistry ; 44(34): 11567-73, 2005 Aug 30.
Article in English | MEDLINE | ID: mdl-16114893

ABSTRACT

Beta-APP cleaving enzyme (BACE) is responsible for the first of two proteolytic cleavages of the APP protein that together lead to the generation of the Alzheimer's disease-associated Abeta peptide. It is widely believed that halting the production of Abeta peptide, by inhibition of BACE, is an attractive therapeutic modality for the treatment of Alzheimer's disease. BACE is an aspartyl protease, and there is significant effort in the pharmaceutical community to apply traditional design methods to the development of active site-directed inhibitors of this enzyme. We report here the discovery of a ligand binding pocket within the catalytic domain of BACE that is distinct from the enzymatic active site (i.e., an exosite). Peptides, initially identified from combinatorial phage peptide libraries, contain the sequence YPYF(I/L)P(L/I) and bind specifically to this exosite, even in the presence of saturating concentrations of active site-directed inhibitors. Binding of peptides to the BACE exosite leads to a concentration-dependent inhibition of proteolysis for APP-related, protein-based substrates of BACE. The discovery of this exosite opens new opportunities for the identification and development of novel and potentially selective small molecule inhibitors of BACE that act through exosite, rather than active site, binding interactions.


Subject(s)
Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/metabolism , Amino Acid Sequence , Amyloid Precursor Protein Secretases , Binding Sites , Binding, Competitive , Catalytic Domain , Endopeptidases , Fluorescence Polarization , Humans , Kinetics , Peptide Fragments/chemistry
14.
Bioorg Med Chem Lett ; 14(10): 2493-7, 2004 May 17.
Article in English | MEDLINE | ID: mdl-15109639

ABSTRACT

Exchange of the ethylene tether in a series of pyridopyrimidine-based MexAB-OprM specific efflux pump inhibitors to an amide bond stabilized the olefin of the acrylic acid moiety, preventing facile photoisomerization to the Z-isomer. Furthermore, the activity was drastically improved in the amide tether variants, providing extremely potent acrylic acid and vinyl tetrazole analogues.


Subject(s)
Bacterial Outer Membrane Proteins/antagonists & inhibitors , Drug Resistance, Bacterial/drug effects , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Pseudomonas aeruginosa/drug effects , Acrylates/pharmacology , Drug Stability , Isomerism , Microbial Sensitivity Tests , Photochemistry , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 14(2): 475-9, 2004 Jan 19.
Article in English | MEDLINE | ID: mdl-14698185

ABSTRACT

The addition of substituents to the pyridopyrimidine scaffold of MexAB-OprM specific efflux pump inhibitors was explored. As predicted by a pharmacophore model, the incorporation substituents at the 2-position improved potency. Piperidines were found to be optimal, and further introduction of polar groups without compromising the activity was shown to be feasible. Careful positioning of the essential acidic moiety of the pharmacophore relative to the scaffold led to the discovery of vinyl tetrazoles with still greater potency.


Subject(s)
Bacterial Outer Membrane Proteins/antagonists & inhibitors , Carrier Proteins/antagonists & inhibitors , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Pseudomonas aeruginosa/physiology , Pyrimidines/chemistry , Bacterial Outer Membrane Proteins/metabolism , Carrier Proteins/metabolism , Membrane Transport Proteins/metabolism , Protein Binding/physiology , Pseudomonas aeruginosa/chemistry , Pyrimidines/metabolism
16.
Annu Rep Med Chem ; 39: 211-221, 2004.
Article in English | MEDLINE | ID: mdl-32287465

ABSTRACT

This chapter introduces four chemical warfare agents: bacillus anthracis (anthrax), yersinia pestis (plague), variola major (smallpox), and francesella tularensis (tularemia). Anthrax is a dimorphic bacterium that normally exists as spores. The clinical presentation can be as cutaneous, inhalational or gastrointestinal forms that are fortuitously not transmissible from person to person. The insidious nature of anthrax has both vegetative and spore morphology. The vegetative state, being the growth phase, is typically responsive to most classes of antibiotics, while the spore phase is not. Plague is caused by a bacterium carried by a rodent flea. While current antibiotics are effective against plague, the worry is the possibility of a bioengineered chimeric construct that would be resistant to all classes of antibiotics. Tularemia is a zoonosis that occurs naturally in the United States, with animal transmission to man. Sometimes an insect vector may also be the primary route of infection. It is highly pathogenic and the inhalation of 10 organisms would be adequate for infection. Smallpox is the most feared of all biowarfare pathogens, primarily due to its high transmissibility versus other pathogens whose etiologic affects are episodic.

18.
Bioorg Med Chem Lett ; 13(23): 4205-8, 2003 Dec 01.
Article in English | MEDLINE | ID: mdl-14623002

ABSTRACT

Problems of low solubility, high serum protein binding, and lack of efficacy in vivo in first generation MexAB-OprM specific efflux pump inhibitors were addressed. Through the use of pharmacophore modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements were arrayed gave second generation leads with greatly improved physical properties and activity in the potentiation of antibacterial quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Outer Membrane Proteins/metabolism , Biological Transport, Active/drug effects , Carrier Proteins/metabolism , Membrane Transport Proteins/metabolism , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/metabolism , Animals , Anti-Bacterial Agents/metabolism , Drug Resistance, Microbial , Fluoroquinolones/pharmacology , Gene Expression Regulation, Bacterial , Lactams/metabolism , Levofloxacin , Mice , Microbial Sensitivity Tests , Neutropenia/drug therapy , Ofloxacin/pharmacology , Protein Binding , Rats , Sepsis/drug therapy , Serum Albumin/metabolism , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 13(19): 3305-9, 2003 Oct 06.
Article in English | MEDLINE | ID: mdl-12951115

ABSTRACT

Dihydropacidamycins having an antibacterial spectrum modified from that of the natural product pacidamycins and mureidomycins have been synthesized. Synthetic dihydropacidamycins with noteworthy antibacterial activity against wild-type and resistant Escherichia coli have been identified (MIC=4-8 microg/mL). Some dihydropacidamycins are shown to have activity against multi-resistant clinical strains of Mycobacterium tuberculosis. Compounds of this class are inhibitors of the cell wall biosynthetic enzyme, MraY.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Peptides/chemical synthesis , Peptides/pharmacology , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Gram-Negative Aerobic Bacteria/drug effects , Gram-Negative Aerobic Bacteria/growth & development , Humans
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