Mirko Buchholz

Mirko Buchholz
PerioTrap Pharmaceuticals GmbH

PhD

About

56
Publications
5,866
Reads
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513
Citations
Additional affiliations
October 2020 - present
PerioTrap Pharmaceuticals GmbH
Position
  • CEO/CSO
October 2013 - September 2020
Fraunhofer Institute for Cell Therapy and Immunology IZI
Position
  • Head of Department
Description
  • Our department is a subsidiary of the IZI and is located in Halle(Saale).
October 2013 - September 2020
University of Leipzig
Position
  • Lecturer
Description
  • I do lectures in the history of pharmacy, pharmaceutical analytics and work as a practical course advisor in medicinal chemistry
Education
August 2003 - September 2007
Martin Luther University of Halle-Wittenberg AND Probiodrug AG
Field of study
  • Medicinal and Computational Chemistry
October 2001 - March 2002
Martin Luther University Halle-Wittenberg
Field of study
  • Medicinal Chemistry
October 1997 - September 2001

Publications

Publications (56)
Article
Full-text available
Periodontitis is a severe yet underestimated oral disease. Since it is linked to several systemic diseases, such as diabetes, artheriosclerosis, and even Alzheimer’s disease, growing interest in treating periodontitis has emerged recently. The major cause of periodontitis is a shift in the oral microbiome. A keystone pathogen that is associated wit...
Article
Full-text available
The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer Disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia represent attractive t...
Article
Full-text available
The development of a targeted therapy would significantly improve the treatment of periodontitis and its associated diseases including Alzheimer Disease, rheumatoid arthritis, and cardiovascular diseases. Glutaminyl cyclases (QCs) from the oral pathogens Porphyromonas gingivalis, Tannerella forsythia and Prevotella intermedia represent attractive t...
Article
Full-text available
Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug discovery efforts led to the development of the first potent and selective inhibitors in the last years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or...
Article
Full-text available
Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin‐B and the cortical granule‐based proteinase ovastacin as novel key‐mechanism in the regulation of fertilization....
Article
Amyloidogenic plaques are hallmarks of Alzheimer’s disease (AD) and typically consist of high percentages of modified Aβ peptides bearing N-terminally cyclized glutamate residues. The human Zinc-(II) enzyme glutaminyl cyclase (QC) was shown in vivo to catalyse the cyclization of N-terminal glutamates of Aβ peptides in a pathophysiological side reac...
Article
We describe the development of flexible minocycline-lipid-complex extrudates with optimized mechanical and drug release properties. These extrudates contain a minocycline – magnesium stearate chelate complex with a higher stability in aqueous media, which has now been incorporated in a PEG-PLGA (polyethylene glycol - poly(lactic-co-glycolic acid))...
Patent
Full-text available
The present invention generally relates to controlled release of tetracycline antibiotics. Specifically, it relates to a com­plex comprising a tetracycline compound (TC) or a pharmaceutically acceptable salt, hydrate or solvate thereof and a divalent metal carboxylate; a pharmaceutical preparation comprising the complex, methods for manufacturing t...
Article
Full-text available
Periodontal therapy using antimicrobials that are topically applied requires slow or controlled release devices. The in vitro antimicrobial activity of biodegradable polymer formulations that contain a new minocycline lipid complex (P-MLC) was evaluated. The new P-MLC formulations that contained 11.5% minocycline were compared with pure minocycline...
Preprint
p>Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin-B and the cortical granule-based proteinase ovastacin as novel key-mechanism in the regulation of fertilizatio...
Preprint
Despite huge progress in hormonal therapy and improved in vitro fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin-B and the cortical granule-based proteinase ovastacin as novel key-mechanism in the regulation of fertilization....
Patent
Full-text available
The present invention relates to novel compounds which are particularly useful as inhibitors of bacterial glutaminyl cyclases (bacQC); pharmaceutical compositions comprising such compounds; compounds and/or pharmaceutical compositions for use in methods for treatment, in particular for use in the treatment of periodontitis and related conditions; a...
Article
Thia analogs of fosmidomycin are potent inhibitors of the non-mevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC, Dxr) of Plasmodium falciparum. Several new thioethers displayed antiplasmodial in vitro activity in the low nanomolar range, without apparent cytotoxic effects in HeLa cells. The (S)-(+)-enan...
Article
Objectives Human glutaminyl cyclases (QC and isoQC) play an important role in maintaining inflammatory conditions. Meanwhile a glutaminyl cyclase synthesized by Porphyromonas gingivalis (PgQC), a key pathogen in developing periodontitis and a potential link of periodontitis with rheumatoid arthritis (RA), was discovered. This study was aimed to de...
Article
The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer's disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopep...
Article
Metalloproteinases of the astacin family are more and more drawing attention as potential drug targets. However, the knowledge about inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is a high selectivity to avoid side effects through the inhibition of off‐target proteases and the interference wi...
Patent
Full-text available
The present invention relates to bacterial glutaminyl cyclases and inhibitors thereof for use in the treatment of periodontitis and related conditions, and provides a bacterial glutaminyl cyclase (bacQC); an antibody which recognizes the bacQC, a method for identifying an inhibitor of the bacQC; a compound according to Formula (I); a pharmaceutical...
Article
The metalloproteinase meprin β emerged as current drug target for the treatment of a number of disorders, among those fibrosis, inflammatory bowel disease and Morbus Alzheimer. A major obstacle in the development of metalloprotease inhibitors is target selectivity to avoid side effects by blocking related enzymes with physiological functions. Here,...
Article
Full-text available
Colicins are natural non-antibiotic bacterial proteins with a narrow spectrum but an extremely high antibacterial activity. These proteins are promising food additives for the control of major pathogenic Shiga toxin-producing E. coli serovars in meats and produce. In the USA, colicins produced in edible plants such as spinach and leafy beets have a...
Patent
Full-text available
The present invention relates to novel hydroxamic acid derivatives as inhibitors of meprin β and/or α, pharmaceutical compositions comprising such compounds, methods for treatment or prophylaxis of diseases or conditions, especially such that are related to meprin β and/or α, and compounds and pharmaceutical compositions for use in such methods.
Article
Structural optimization of 3-hydroxy-N′-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of Plasmodium falciparum, excellent parasite selectivity and nanomolar activity against the earliest forms of gametocyte development. Particularly, derivatives with a 1,3-dih...
Article
The astacin proteases meprin α and β are emerging drug targets for treatment of disorders such as kidney failure, fibrosis or inflammatory bowel disease. However, there are only few inhibitors of both proteases reported to date. Starting from NNGH as lead structure, a detailed elaboration of the structure-activity relationship of meprin β inhibitor...
Article
Full-text available
In recent years, many new enzymes, like glutaminyl cyclase (QC), could be associated with pathophysiological processes and represent targets for many diseases, so that enzyme-inhibiting properties of natural substances are becoming increasingly important. In different studies, the pathophysiology connection of QC to various diseases including Alzhe...
Conference Paper
Many proteins of the posttranslational processing machinery, such as glycosyltransferases and the recently discovered isoenzyme of glutaminyl cyclase (QC), are localized in the Golgi apparatus. Thereby the retention of proteins in the Golgi is a common sorting signal for the cell. For yeast it is well known, that the cytosolic protein Vps74 causes...
Patent
Full-text available
Compounds of formula (I), combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: R1 represents and R2, R3, R4, R5, R6, X1, X2, X3, X4, Y and Z are as defined throughout the description and the claims.
Conference Paper
Full-text available
N-terminally truncated Amyloid beta (Aβ) peptides constitute a major part of Aβ-peptides accumulating in the brains of Alzheimer’s disease (AD) patients. In particular, pyroglutamate (pE, pGlu) -modified Aβ-peptides, Aβ3pE-40/42 and Aβ11pE-40/42, have been shown to correlate with disease progression. It has been extensively shown that pGlu-Aβ, due...
Conference Paper
Glutaminyl Cyclases are responsible for the formation of pyroglutamyl residues at the N-terminus of peptides out of glutamines and glutamates. Recently N-truncated forms of pyroglutamylated Aβ-peptides came into the focus of Alzheimer’s Disease (AD) research. The reason is their enforced amyloidogenicity, likely contributing to progression of the d...
Patent
Full-text available
Provided herein are methods for treating and preventing neurodegenerative disease in a mammal by administering an inhibitor of glutaminyl cyclase (QC). Neurodegenerative diseases treatable or preventable according to methods described herein include mild cognitive impairment (MCI), Alzheimer's disease, neurodegeneration in Down Syndrome, Familial B...
Patent
Full-text available
The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, wherein R1, R2, R3, R4 and R5 are as defined herein, as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of N- terminal glutamine res...
Conference Paper
N-terminally truncated Ab peptides constitute a major part of Aβ accumulating in Alzheimers disease (AD). In particular, pyroglutamate (pE, pGlu)-modified Aβ, Aβ3pE-40/42 and Aβ11pE-40/42, have been shown to correlate with disease progression and being overrepresented in early-onset forms of inherited AD. Recently, we could show that Aβ3pE-40/42 fo...
Article
Full-text available
Glutaminyl cyclase (hQC) has emerged as a new potential target for the treatment of Alzheimer’s Disease (AD). The inhibition of hQC prevents of the formation of the Aβ3(pE)-40,42-species which were shown to be of elevated neuro-toxicity and are likely to act as a seeding core leading to an accelerated formation of Aβ-oligomers and fibrils. This wor...
Article
Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate-modified amyloid peptides deposited in neurodegenerative disorders such as Alzheimer's disease. Inhibitors of QC are currently in development as potential therapeutics. The crystal structures of the potent inhibitor PBD150 bound to human and murine QC (hQC, mQC) have been described r...
Article
Glutaminyl cyclases (QCs), which catalyze the formation of pyroglutamic acid (pGlu) at the N-terminus of a variety of peptides and proteins, have attracted particular attention for their potential role in Alzheimer's disease. In a transgenic Drosophila melanogaster (Dm) fruit fly model, oral application of the potent competitive QC inhibitor PBD150...
Conference Paper
Glutaminyl Cyclases have been identified as catalysts of pyroglutamyl formation at the N-terminus of Aβ-peptides deposited in Alzheimers Disease. The modification enforces amyloidogenicity, likely contributing to progression of the disorder. Inhibitors of QC attenuated AD-like pathol. in animal models of AD. We characterized the binding mode of the...
Conference Paper
The S/T kinase CDK9 is part of the P-TEFb complex which promotes the productive transcriptional elongation via phosphorylation of serine-2 residues within the RNA polymerase II C-terminal repeat domain. P-TEFb, recruited to responsive promoters via binding to transcription factors or chromatin assocd. proteins (e.g. NF-kB), is specifically required...
Article
Formation of N-terminal pyroglutamate (pGlu or pE) from glutaminyl or glutamyl precursors is catalyzed by glutaminyl cyclases (QC). As the formation of pGlu-amyloid has been linked with Alzheimer's disease, inhibitors of QCs are currently the subject of intense development. Here, we report three crystal structures of N-glycosylated mammalian QC fro...
Conference Paper
The progression of the Alzheimer's disease (AD) pathol. is hallmarked by the deposition of Amyloid-plaques contg. the amyloid-beta peptide (Aβ). This process is paralleled by a loss of neuronal functionality of the brain due to inflammatory events. Up to date, no causal treatment is known, that influences both of these pathol. processes. N-terminal...
Conference Paper
Cyclin-Dependent Kinase 9 (CDK9) is an ubiquitously expressed serine/threonine kinase. In complex with Cyclin-T, it is an essential part of the Pos. Transcription Elongation Factor β (P-TEFβ). P-TEFβ is recruited to promote RNA-Polymerase II processivity by serine 2 phosphorylation in ist C-terminal domain. In addn., it was shown, that NF-κB depend...
Article
Full-text available
Nitrogen is one of the most prominent hetero atoms found in heterocycles. The corresponding electron lone pairs of these nitrogen atoms are mainly responsible for properties like the basicity and the pkb-values of the investigated heterocycle. Nevertheless, the overall electronic state of a molecule is also directly related to observable physico-ch...
Patent
The present invention relates to compounds of formula (I), combinations and uses thereof for disease therapy, R1 represents heteroaryl, -carbocyclyl-heteroaryl, -alkenylheteroaryl or -alkylheteroaryl; R2 represents hydrogen; halogen; alkenyl; alkynyl; -alkenylaryl; -alkenylheteroaryl; alkyl, which may optionally be substituted by one or more groups...
Article
The inhibition of human glutaminyl cyclase (hQC) has come into focus as a new potential approach for the treatment of Alzheimer's disease. The hallmark of this principle is the prevention of the formation of Abeta(3,11(pE)-40,42), as these Abeta-species were shown to be of elevated neurotoxicity and likely to act as a seeding core leading to an acc...
Patent
Full-text available
The present invention relates to compds. of formula I, combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: R1 represents (un)substituted imidazolyl or benzimidazolyl and X1-X4 are independently C, N, O, or S. A process for...
Patent
Full-text available
The present invention relates to compds. of formula I, combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers thereof wherein: A represents (un)substituted imidazolyl or benzimidazolyl; and B is H or Me; and R1 is alkyl, alkenyl, etc. A proces...
Patent
Full-text available
The present invention relates to compds. of formula I, combinations and uses thereof for disease therapy, or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers, stereoisomers and polymorphs thereof, wherein A is (un)substituted imidazolyl or benzimidazolyl; B is H or Me; and R1 is alkyl, alkenyl, etc. A proces...
Patent
Full-text available
The title compds. with general formula I [wherein R1 = (un)substituted alkyl, aryl, heteroaryl, heterocyclyl, etc.; R2, R3, and R4 = independently H, alkyl, or halogen] or pharmaceutically acceptable salts or solvates thereof, including all tautomers, stereoisomers and polymorphs thereof, were prepd. as inhibitors of glutaminyl cyclase. For example...
Article
Modified amyloid beta (Abeta) peptides represent major constituents of the amyloid deposits in Alzheimer's disease and Down's syndrome. In particular, N-terminal pyroglutamate (pGlu) following truncation renders Abeta more stable, increases hydrophobicity and the aggregation velocity. Recent evidence based on in vitro studies suggests that the cycl...
Patent
Full-text available
Title compds. represented by the formula I [wherein R1 = heteroaryl, -carbocyclylheteroaryl, -alkenylheteroaryl or -alkylheteroaryl; R2 = alkyl, carbocyclyl, alkenyl, etc.; X = S or NR3; R3 = H or alkyl; with the proviso; and pharmaceutically acceptable salts, polymorphs, tautomers, stereoisomers or solvates thereof] were prepd. as inhibitors of gl...
Patent
Full-text available
The present invention provides novel physiol. substrates of mammalian glutaminyl cyclase (QC, EC 2.3.2.5), new effectors of QC, methods for screening for such effectors, and the use of such effectors and pharmaceutical compns. comprising such effectors for the treatment of conditions that can be treated by modulation of QC-activity. Such conditions...
Article
The first effective inhibitors for human glutaminyl cyclase (QC) are described. The structures are developed by applying a ligand-based optimization approach starting from imidazole. Screening of derivatives of that heterocycle led to compounds of the imidazol-1-yl-alkyl thiourea type as a lead scaffold. A library of thiourea derivatives was synthe...
Article
Murine glutaminyl cyclase (mQC) was identified in the insulinoma cell line beta-TC 3 by determination of enzymatic activity and RT-PCR. The cloned cDNA was expressed in the secretory pathway of the methylotrophic yeast Pichia pastoris and purified after fermentation using a new three-step protocol. mQC converted a set of various substrates with ver...
Patent
Full-text available
Title compds. [I; A = (Ph-, cycloalkyl-interrupted) alkylene, alkenylene, alkynylene; B = NHC(:X)NHD, C(:X)NHD, C(:X)SD, etc.; D = alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocyclyl, etc.; X = O, S, imino, (substituted) CH2], with specific exceptions, were prepd. Thus, 3,4-methylenedioxyphenyl isothiocyanate and 3-(1H-imidazol-1-yl)propy...
Patent
Full-text available
Title compds. I [A = alkyl, alkenyl, alkynyl, etc.; B = substituted thiourea, urea, amide, etc.] and their pharmaceutical acceptable salts, are prepd. and disclosed as glutaminyl cyclase inhibitors. Thus, e.g., II was prepd. by coupling of 1H-imidazole-1-propanamine with the corresponding isothiocyanate. The inhibitory activity of I towards DP IV w...
Patent
Full-text available
The present invention relates to compds. that act as inhibitors of QC and combinations thereof for the treatment of neuronal disorders, esp. Alzheimer's disease, Down's syndrome, Parkinson's disease, Huntington's chorea, pathogenic psychotic conditions, schizophrenia, impaired food intake, sleep-wakefulness, impaired homeostatic regulation of energ...

Projects

Projects (3)
Project
We develop new approaches for the treatment of an underestimated, but one of the most prevalent disease.
Project
Our aim is the discovery and development of inhibitors for proteases of the astacin family, e.g. meprins.
Project
We support our partners with our knowledge and expertise in the analytics of small molecules in their research and development programs due to the establishment of the corresponding methods covering their specific needs.