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1.
ChemMedChem ; 4(12): 2054-9, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19816894

ABSTRACT

Diverse serine and cysteine proteases as well as alkaline proteinases and elastases play a crucial role in numerous biological processes. Natural peptide aldehydes such as the "microbial alkaline proteinase inhibitor" (MAPI, 1) are valuable tools to characterize novel enzymes and to study their function in nature. Within a drug discovery program we wanted to design and explore non-natural MAPI congeners with novel biological profiles. To that end we devised a simple, practical, and scalable synthesis of MAPI 1 from readily available amino acid building blocks. The modular nature of our approach allows convenient structural modification of the MAPI backbone.


Subject(s)
Bacterial Proteins/antagonists & inhibitors , Peptides/chemical synthesis , Amino Acids/chemistry , Bacterial Proteins/metabolism , Endopeptidases/metabolism , Models, Molecular , Molecular Structure , Peptides/pharmacology , Protein Binding
3.
Angew Chem Int Ed Engl ; 48(19): 3397-400, 2009.
Article in English | MEDLINE | ID: mdl-19294713

ABSTRACT

Form and function: The natural product myxopyronin A provides the key to understanding the inhibition of bacterial RNA polymerase and should spark new ideas for the design of new antibiotics against tuberculosis and other infectious diseases.


Subject(s)
Antibiotics, Antitubercular/chemistry , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Lactones/chemistry , Mycobacterium tuberculosis/drug effects , Transcription, Genetic/drug effects , Antibiotics, Antitubercular/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Lactones/pharmacology , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/genetics
5.
Antimicrob Agents Chemother ; 49(3): 987-95, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15728893

ABSTRACT

Novel N-3-alkylated 6-anilinouracils have been identified as potent and selective inhibitors of bacterial DNA polymerase IIIC, the enzyme essential for the replication of chromosomal DNA in gram-positive bacteria. A nonradioactive assay measuring the enzymatic activity of the DNA polymerase IIIC in gram-positive bacteria has been assembled. The 6-anilinouracils described inhibited the polymerase IIIC enzyme at concentrations in the nanomolar range in this assay and displayed good in vitro activity (according to their MICs) against staphylococci, streptococci, and enterococci. The MICs of the most potent derivatives were about 4 microg/ml for this panel of bacteria. The 50% effective dose of the best compound (6-[(3-ethyl-4-methylphenyl)amino]-3-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}uracil) was 10 mg/kg of body weight after intravenous application in a staphylococcal sepsis model in mice, from which in vivo pharmacokinetic data were also acquired.


Subject(s)
Anti-Bacterial Agents/pharmacology , DNA Polymerase III/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Gram-Positive Bacteria/enzymology , Animals , DNA/biosynthesis , Dogs , Enzyme Inhibitors/pharmacokinetics , Female , Gram-Positive Bacteria/drug effects , Male , Mice , Microbial Sensitivity Tests , Rats , Rats, Wistar , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymology , Structure-Activity Relationship
6.
Antimicrob Agents Chemother ; 48(2): 525-32, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14742205

ABSTRACT

Phenylalanyl (Phe)-tRNA synthetase (Phe-RS) is an essential enzyme which catalyzes the transfer of phenylalanine to the Phe-specific transfer RNA (tRNA(Phe)), a key step in protein biosynthesis. Phenyl-thiazolylurea-sulfonamides were identified as a novel class of potent inhibitors of bacterial Phe-RS by high-throughput screening and chemical variation of the screening hit. The compounds inhibit Phe-RS of Escherichia coli, Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus, with 50% inhibitory concentrations in the nanomolar range. Enzyme kinetic measurements demonstrated that the compounds bind competitively with respect to the natural substrate Phe. All derivatives are highly selective for the bacterial Phe-RS versus the corresponding mammalian cytoplasmic and human mitochondrial enzymes. Phenyl-thiazolylurea-sulfonamides displayed good in vitro activity against Staphylococcus, Streptococcus, Haemophilus, and Moraxella strains, reaching MICs below 1 micro g/ml. The antibacterial activity was partly antagonized by increasing concentrations of Phe in the culture broth in accordance with the competitive binding mode. Further evidence that inhibition of tRNA(Phe) charging is the antibacterial principle of this compound class was obtained by proteome analysis of Bacillus subtilis. Here, the phenyl-thiazolylurea-sulfonamides induced a protein pattern indicative of the stringent response. In addition, an E. coli strain carrying a relA mutation and defective in stringent response was more susceptible than its isogenic relA(+) parent strain. In vivo efficacy was investigated in a murine S. aureus sepsis model and a S. pneumoniae sepsis model in rats. Treatment with the phenyl-thiazolylurea-sulfonamides reduced the bacterial titer in various organs by up to 3 log units, supporting the potential value of Phe-RS as a target in antibacterial therapy.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacteria/enzymology , Enzyme Inhibitors/pharmacology , Animals , Bacillus subtilis/drug effects , Bacillus subtilis/genetics , CHO Cells , Colony Count, Microbial , Cricetinae , Drug Design , Escherichia coli/drug effects , Escherichia coli/enzymology , Female , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Pneumococcal Infections/drug therapy , Pneumococcal Infections/microbiology , Proteome/genetics , Rats , Rats, Wistar , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Substrate Specificity
7.
Science ; 299(5608): 893-6, 2003 Feb 07.
Article in English | MEDLINE | ID: mdl-12574631

ABSTRACT

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.


Subject(s)
Acetylcysteine/analogs & derivatives , Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Nucleocapsid/metabolism , Pyridines/pharmacology , Pyrimidines/pharmacology , Triazoles/pharmacology , Acetylcysteine/pharmacology , Amino Acid Substitution , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Binding Sites , Capsid/metabolism , DNA Replication/drug effects , DNA, Viral/biosynthesis , Half-Life , Hepatitis B Virus, Duck/drug effects , Hepatitis B Virus, Duck/metabolism , Hepatitis B virus/physiology , Humans , Mutation , Pyridines/chemistry , Pyridines/metabolism , Pyrimidines/chemistry , Pyrimidines/metabolism , Recombinant Proteins/metabolism , Stereoisomerism , Triazoles/chemistry , Triazoles/metabolism , Tumor Cells, Cultured , Viral Core Proteins/chemistry , Viral Core Proteins/genetics , Viral Core Proteins/metabolism , Virus Assembly/drug effects , Virus Replication/drug effects
8.
Nat Med ; 8(4): 392-8, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11927946

ABSTRACT

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.


Subject(s)
Antiviral Agents/therapeutic use , DNA Helicases/antagonists & inhibitors , Enzyme Inhibitors/therapeutic use , Herpes Simplex/drug therapy , Pyridines/therapeutic use , Thiazoles/therapeutic use , Acyclovir/therapeutic use , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , DNA Primase , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Female , Guinea Pigs , Herpes Simplex/enzymology , Herpes Simplex/pathology , Humans , Infant, Newborn , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Pregnancy , Pyridines/chemistry , Pyridines/pharmacokinetics , Safety , Sulfonamides , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Viral Proteins
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