Drug Design and Optimisation
Prof Dr Anna K. H. Hirsch
The Hirsch group adopts a target-based rational design strategy focusing on biologically relevant, often underexplored enzymes, transporters and regulators within bacterial and parasitic pathogens. The group employs a variety of biophysical methods to investigate compound–target interactions and has established several in vitro and cell-based assays for straightforward evaluation of novel anti-infectives and multiparameter optimisation.
Our research and approach
The emergence of drug-resistant strains of human pathogens such as P. aeruginosa, S. aureus or S. pneumoniae is a recognised threat to human health and urgently calls for the development of new antibacterial agents with novel modes of action. The department DDOP adopts a target-based strategy focussing on a portfolio of two types of drug targets.
The first group comprises targets which impair vital mechanisms within the bacteria and effectively kill them. One example is the enzyme DXS which plays a crucial role in the methylerythritol phosphate pathway, which is essential for the biosynthesis of universal isoprenoid precursors in many gram-negative pathogens, but absent from humans. The second group comprises targets interfering with pathogenicity and virulence without affecting bacterial viability. These pathoblockers are believed to cause a lower rate of resistance development, whilst leaving the commensal microbiota untouched.
The Hirsch group applies a series of established hit-identification strategies, including structure- and fragment-based drug design, classical medicinal chemistry and virtual screening. In addition, pioneering of innovative protein-templated methods such as dynamic combinatorial chemistry and kinetic target-guided synthesis in terms of the scope of chemical reactions, biological targets and synergistic combinations addresses key bottlenecks. Use of established and innovative techniques to design, synthesize and profile the most promising inhibitors enables efficient subsequent multiparameter optimisation as well as elucidation of the mode of action.
Scientists in the interdisciplinary team have diverse backgrounds such as medicinal chemistry, synthetic organic chemistry, pharmacy, pharmacology, biology or biochemistry, resulting in a diverse skill set.
Team members

Prof Dr Anna K. H. Hirsch
Group Leader

Annette Herkströter
Secretary

Lisa Marie Andre
Secretary

Dr Jörg Haupenthal
Scientist

Dr Ahmed S. Abdelsamie
Postdoc

Dr Alexander Kiefer
Postdoc

Dr Andreas Kany
Postdoc

Dr Eleonora Diamanti
Postdoc

Dr Jelena Konstantinović
Postdoc

Dr Mostafa Hamed
Postdoc

Dr Ravindra P. Jumde
Postdoc

Dr Sangeun Lee
Postdoc

Dr Sebastian Adam
Postdoc

Dr Walid A. M. Elgaher
Postdoc

Alaa Alhayek
PhD Student

Andreas Klein
PhD Student

Antoine Lacour
PhD Student

Cansu Kaya
PhD Student

Christina Kosch
PhD Student

Daan Willocx
PhD Student

Federica Mancini
PhD Student

Henni-Karoliina Ropponen
PhD Student

Ioulia Antonia Exapicheidou
PhD Student

Lara Rosenberger
PhD Student

Sandra Johannsen
PhD Student

Spyridon Bousis
PhD Student

Uladzislau Hapko
PhD Student

Zhoor Hamid
PhD Student

Dennis Jener
Technical Assistant

Jeannine Jung
Technical Assistant

Selina Wolter
Technical Assistant

Simone Amann
Technical Assistant

Tabea Schramm
Technical Assistant
Research projects
Due to the rapidly increasing number of pathogenic bacteria being resistant to common antibiotics, the development of new antibacterial agents is urgently needed. To address these problems, the Hirsch group adopts a strategy based on the rational design and synthesis of anti-infectives with novel modes of action. In this context, the group is focusing on a portfolio of biologically relevant, ideally underexplored enzymes, transporters and regulators within bacterial pathogens. These drug targets can be grouped into those that impair vital mechanisms within the bacterium and effectively kill them (e.g., ECF-T, DnaN and DXS) and those that interfere with the pathogenicity and virulence without affecting bacterial viability (e.g., ColH and LasB).
The group employs a variety of biophysical methods to identify novel hit compounds and to investigate compound–target interactions. Various in vitro and cell-based assays, the generation of in silico data and the co-crystallization of selected compounds with their targets support the straightforward evaluation of novel anti-infectives and their further optimisation by classical and innovative medicinal chemistry approaches.
Below you will find an overview of selected targets we are currently addressing and to which we apply the above-mentioned strategies:
ECF-T
The energy-coupling factor (ECF) transporters are a family of transmembrane proteins involved in the uptake of vitamins by a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of organisms that depend on vitamin uptake, including pathogenic species such as Staphylococcus aureus, Streptococcus pneumoniae and Enterococcus faecium. As these bacteria cannot synthesize important vitamins such as folic acid, pantothenate and niacin de novo, they depend on ECF transporters to take them up from the environment. Due to this central role in the metabolism of bacteria, ECF transporters are novel potential antimicrobial targets to tackle infection. Recently we identified the first classes of selective antibacterial agents showing promising inhibition of the ECF transporters. We are currently trying to further develop these compounds.
MEP pathway (target: DXS, IspE):
The methyl erythritol phosphate (MEP) pathway is a rich, underexplored source of anti-infective targets that are absent from humans but essential in many pathogenic bacteria, protozoa and plants. This opens up the possibility of developing highly selective inhibitors that are active against clinically relevant pathogens such as four ESKAPE pathogens: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp., all of which have highest priority according to the WHO Global Priority List of antibiotic-resistant bacteria – as well as Mycobacterium tuberculosis and Plasmodium falciparum. In these pathogens, the MEP pathway is the sole source of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). The latter are the universal building blocks for the biosynthesis of isoprenoids, a large and diverse class of natural products fulfilling a myriad of indispensable functions. With DXS, IspD, IspE we address three essential enzymes of this pathway. Our best compounds are highly active against the mentioned pathogens and show nanomolar IC50 values.
DnaN
Antibacterial drugs targeting essential multi-enzyme complexes are less prone to resistance development, since their malfunctioning is hard to bypass. In this context, the bacterial replisome machinery, which consists of at least twelve interacting enzymes that are highly conserved in bacteria, contains several attractive and promising antibacterial targets – including the bacterial β-sliding clamp DnaN. DnaN is a crucial subunit of the DNA polymerase III holoenzyme, preventing polymerase dissociation and enhancing polymerase activity. Furthermore, the β-sliding clamp shows interactions with a variety of other enzymes involved in replication and DNA repair processes. Its important functionality in the replication process and its highly conserved structure across bacterial species and its significant structural divergence to the mammalian counterpart (PCNA) make DnaN an attractive target for the treatment of various pathogens including Mycobacterium tuberculosis. Based on the natural product griselimycin (GM), a known DnaN binder, we adopted a semisynthetic approach, which resulted in a set of GM derivatives with promising antibacterial activities. Furthermore, we identified diverse small organic molecules binding to DnaN. The optimization of the most promising compounds is ongoing.

ColH
Clostridia represent a family of ubiquitously occurring gram-positive bacteria comprising perilous pathogens causing serious infectious diseases. The high lethality of these bacteria is related to collagenases, which are crucial for clostridial virulence, given their critical role in colonisation and evasion of host immune defence, acquisition of nutrients, facilitation of dissemination, or tissue damage during infection. The inhibition of these extracellular collagenases is conceptually attractive, as it does not attack the pathogen directly but rather blocks the colonisation and infiltration of the host by the clostridia. Targeting extracellular enzymes has the added benefit that inhibitors do not need to cross the bacterial cell wall, which has been challenging in many cases. Clostridial collagenases are zinc metalloproteinases with a multi-domain organisation, homologues of which are also found in many bacilli. Our group was the first who published compounds showing not only a highly potent inhibition of clostridial and bacillal collagenases (ColH IC50 in nM range) but also a strong selectivity over human MMPs.

LasB
Pseudomonas aeruginosa (PA), a highly problematic gram-negative pathogen, which has been assigned critical priority by the WHO, is responsible for many nosocomial infections. The opportunistic pathogen is also commonly found in burns, and in lungs of COPD and cystic fibrosis patients. PA-derived virulence factors play pivotal roles in mechanisms mediating its pathogenesis and infectivity. The strategy to develop “pathoblockers” targeting such virulence factors is expected to leave the commensal microbiome intact and to be less prone to the development of resistance compared to conventional antibiotics. One of the major virulence factors of PA is the extracellular zinc-metalloprotease elastase LasB. LasB substantially contributes to disease progression in PA-infected individuals by facilitating host invasion and immune evasion, and was furthermore reported to be involved in the formation of PA biofilms. Inhibition of LasB is a promising strategy to effectively reduce virulence of PA without affecting viability of the pathogen and the host microbiome. Our most promising LasB inhibitors show nanomolar IC50 values and a promising safety profile.

Publications
2021
Identification of a 1-deoxy-D-xylulose-5-phosphate synthase (DXS) mutant with improved crystallographic properties
Gierse R, Reddem E, Alhayek A, Baitinger D, Hamid Z, Jakobi H, Laber B, Lange G, Hirsch A, Groves (2021)
Biochemical and Biophysical Research Communications, 539DOI: 10.1016/j.bbrc.2020.12.069
2020
Enhancing glycan stability via site-selective fluorination: modulating substrate orientation by molecular design
Alexander Axer, Ravindra P. Jumde, Sebastian Adam, Andreas Faust, Michael Schäfers, Manfred Fobker, Jesko Koehnke, Anna K. H. Hirsch, Ryan Gilmour (2020)
Chem. Sci.DOI: 10.1039/D0SC04297H
Frontispiece: Protein‐Templated Hit Identification through an Ugi Four‐Component Reaction
Federica Mancini, M. Yagiz Unver, Walid A. M. Elgaher, Varsha R. Jumde, Alaa Alhayek, Peer Lukat, Jennifer Herrmann, Martin D. Witte, Matthias Köck, Wulf Blankenfeldt, Rolf Müller, Anna K. H. Hirsch (2020)
Chemistry – A European Journal, 26 (64)DOI: 10.1002/chem.202086462
Protein-Templated Hit Identification through an Ugi Four-Component Reaction*
Mancini F, Unver M, Elgaher W, Jumde V, Alhayek A, Lukat P, Herrmann J, Witte M, Köck M, Blankenfeldt W, Müller R, Hirsch A (2020)
Chemistry (Weinheim an der Bergstrasse, Germany), 26 (64): 14585-14593DOI: 10.1002/chem.202002250
A hydrogel-based in vitro assay for the fast prediction of antibiotic accumulation in Gram-negative bacteria
Richter R, Kamal M, García-Rivera M, Kaspar J, Junk M, Elgaher W, Srikakulam S, Gress A, Beckmann A, Grißmer A, …, Schneider-Daum N, Lehr C (2020)
Materials Today BioDOI: 10.1016/j.mtbio.2020.100084
7-Hydroxycoumarins are Affinity-based Fluorescent Probes for Competitive Binding Studies of Macrophage Migration Inhibitory Factor
Xiao Z, Chen D, Song S, van der Vlag R, van der Wouden P, van Merkerk R, Cool R, Hirsch A, Melgert B, Quax W, Poelarends G, Dekker F (2020)
Journal of medicinal chemistryDOI: 10.1021/acs.jmedchem.0c01160
pH-Dependent morphology and optical properties of lysine-derived molecular biodynamers
Lee S, Kaya C, Jang H, Koch M, Loretz B, Buhler E, Lehr C, Hirsch A (2020)
Mater. Chem. Front., 4 (3): 905-909DOI: 10.1039/C9QM00651F
Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach
Markella Konstantinidou, Francesca Magari, Fandi Sutanto, Jörg Haupenthal, Varsha R. Jumde, M. Yagiz Ünver, Andreas Heine, Carlos Jamie Camacho, Anna K. H. Hirsch, Gerhard Klebe, Alexander Dömling (2020)
ChemMedChem, 15 (8): 680-684DOI: 10.1002/cmdc.202000024
Optimized Inhibitors of MDM2 via an Attempted Protein‐Templated Reductive Amination
Vlag R, Yagiz Unver M, Felicetti T, Twarda-Clapa A, Kassim F, Ermis C, Neochoritis C, Musielak B, Labuzek B, Dömling A, Holak T, Hirsch A (2020)
ChemMedChem, 15 (4): 370-375DOI: 10.1002/cmdc.201900574
Validating the 1,2-Difluoro Motif As a Hybrid Bioisostere of CF3 and Et Using Matrix Metalloproteinases As Structural Probes
Erdeljac N, Thiehoff C, Jumde R, Daniliuc C, Höppner S, Faust A, Hirsch A, Gilmour R (2020)
Journal of medicinal chemistry, 63 (11): 6225-6237DOI: 10.1021/acs.jmedchem.0c00648
N -Aryl-3-mercaptosuccinimides as Antivirulence Agents Targeting Pseudomonas aeruginosa Elastase and Clostridium Collagenases
Konstantinovic J, Yahiaoui S, Alhayek A, Haupenthal J, Schönauer E, Andreas A, Kany A, Müller R, Koehnke J, Berger F, …, Brandstetter H, Hirsch A (2020)
J. Med. Chem., 63 (15): 8359-8368DOI: 10.1021/acs.jmedchem.0c00584
Flotillin-mediated membrane fluidity controls peptidoglycan synthesis and MreB movement
Zielinska A, Savietto A, Sousa Borges A, Martinez D, Berbon M, Roelofsen J, Hartman A, Boer R, van der Klei I, Hirsch A, …, Bramkamp M, Scheffers D (2020)
eLife, 9DOI: 10.7554/eLife.57179
Potential Dental Biofilm Inhibitors: Dynamic Combinatorial Chemistry Affords Sugar-Based Molecules that Target Bacterial Glucosyltransferase
Hartman A, Jumde V, Elgaher W, Te Poele E, Dijkhuizen L, Hirsch A (2020)
ChemMedChemDOI: 10.1002/cmdc.202000222
A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d -galactose pentaacetate
Zahorska E, Kuhaudomlarp S, Minervini S, Yousaf S, Lepsik M, Kinsinger T, Hirsch A, Imberty A, Titz A (2020)
Chem. Commun., 56 (62): 8822-8825DOI: 10.1039/d0cc03490h
Enhancing Glycan Stability via Site-Selective Fluorination: Modulating Substrate Orientation by Molecular Design
Axer A, Jumde R, Adam S, Faust A, Schäfers M, Fobker M, Koehnke J, Hirsch A, Gilmour R (2020)
BookDOI: 10.26434/chemrxiv.12656210
Hit-Optimization Using Target-Directed Dynamic Combinatorial Chemistry: Development of Inhibitors of the Anti-Infective Target 1-Deoxy-D-Xylulose-5-Phosphate Synthase
Jumde R, Guardigni M, Gierse R, Alhayek A, Zhu D, Hamed Z, Johannsen S, Elgaher W, Haupenthal J, Hirsch A (2020)
BookDOI: 10.26434/chemrxiv.12681761.v1
Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling
Hollenhorst M, Jurastow I, Nandigama R, Appenzeller S, Li L, Vogel J, Wiederhold S, Althaus M, Empting M, Altmüller J, …, Saliba A, Krasteva-Christ G (2020)
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34 (1): 316-332DOI: 10.1096/fj.201901314RR
BOPC1 Enantiomers Preparation and HuR Interaction Study. From Molecular Modeling to a Curious DEEP-STD NMR Application
Della Volpe S, Listro R, Parafioriti M, Di Giacomo M, Rossi D, Ambrosio F, Costa G, Alcaro S, Ortuso F, Hirsch A, Vasile F, Collina S (2020)
ACS Med. Chem. Lett., 11 (5): 883-888DOI: 10.1021/acsmedchemlett.9b00659
Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening
Diamanti E, Setyawati I, Bousis S, mojas l, Swier l, Haupenthal J, Gibson P, Volz C, stanek w, Jaeger m, …, slotboom d, Hirsch A (2020)
BookDOI: 10.26434/chemrxiv.11728710.v1
Synthesis and Biological Evaluation of Novel 2-Substituted Analogues of (–)-Pentenomycin I
Zisopoulou S, Bousis S, Haupenthal J, Herrmann J, Müller R, Hirsch A, Komiotis D, Gallos J, Stathakis C (2020)
Synlett, 31 (05): 475-481DOI: 10.1055/s-0039-1690772
2019
Comparing the Self-Assembly of Sexiphenyl-Dicarbonitrile on Graphite and Graphene on Cu(111)
Schmidt N, Li J, Gottardi S, Moreno-Lopez J, Enache M, Monjas L, van der Vlag R, Havenith R, Hirsch A, Stöhr M (2019)
Chem. Eur. J., 25 (19): 5065-5070DOI: 10.1002/chem.201806312
Inverting Small Molecule–Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism
Bentler P, Bergander K, Daniliuc C, Mück-Lichtenfeld C, Jumde R, Hirsch A, Gilmour R (2019)
Angewandte Chemie (International ed. in English), 58 (32): 10990-10994DOI: 10.1002/anie.201905452
Spray-drying of inhalable, multifunctional formulations for the treatment of biofilms formed in cystic fibrosis
Lababidi N, Ofosu Kissi E, Elgaher W, Sigal V, Haupenthal J, Schwarz B, Hirsch A, Rades T, Schneider M (2019)
Journal of Controlled Release, 314: 62-71DOI: 10.1016/j.jconrel.2019.10.038
Energy-Coupling Factor Transporters as Novel Antimicrobial Targets
Bousis S, Setyawati I, Diamanti E, slotboom d, Hirsch A (2019)
Adv. Therap., 2 (2)DOI: 10.1002/adtp.201800066
Protein-Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol
Hartman A, Gierse R, Hirsch A (2019)
Eur. J. Org. Chem., 2019 (22): 3581-3590DOI: 10.1002/ejoc.201900327
Concepts and Core Principles of Fragment-Based Drug Design
Kirsch P, Hartman A, Hirsch A, Empting M (2019)
Molecules (Basel, Switzerland), 24 (23)DOI: 10.3390/molecules24234309
Novel Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis, and Interaction Studies
Della Volpe S, Nasti R, Queirolo M, Unver M, Jumde V, Dömling A, Vasile F, Potenza D, Ambrosio F, Costa G, …, Hirsch A, Collina S (2019)
ACS Med. Chem. Lett., 10 (4): 615-620DOI: 10.1021/acsmedchemlett.8b00600
A combinatorial approach for the discovery of drug-like inhibitors of 15-lipoxygenase-1
van der Vlag R, Guo H, Hapko U, Eleftheriadis N, Monjas L, Dekker F, Hirsch A (2019)
European journal of medicinal chemistry, 174: 45-55DOI: 10.1016/j.ejmech.2019.04.021
Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists
Simhadri C, Daze K, Douglas S, Milosevich N, Monjas L, Dev A, Brown T, Hirsch A, Wulff J, Hof F (2019)
ChemMedChem, 14 (15): 1444-1456DOI: 10.1002/cmdc.201900021
Low-Dimensional Metal-Organic Coordination Structures on Graphene
Li J, Solianyk L, Schmidt N, Baker B, Gottardi S, Moreno Lopez J, Enache M, Monjas L, van der Vlag R, Havenith R, Hirsch A, Stöhr M (2019)
The journal of physical chemistry. C, Nanomaterials and interfaces, 123 (20): 12730-12735DOI: 10.1021/acs.jpcc.9b00326
Novel 15-Lipoxygenase-1 Inhibitor Protects Macrophages from Lipopolysaccharide-Induced Cytotoxicity
Guo H, Verhoek I, Prins G, van der Vlag R, van der Wouden P, van Merkerk R, Quax W, Olinga P, Hirsch A, Dekker F (2019)
Journal of medicinal chemistry, 62 (9): 4624-4637DOI: 10.1021/acs.jmedchem.9b00212
Replacement of an Indole Scaffold Targeting Human 15-Lipoxygenase-1 Using Combinatorial Chemistry
Prismawan D, van der Vlag R, Guo H, Dekker F, Hirsch A (2019)
HCA, 102 (5)DOI: 10.1002/hlca.201900040
Reversible immobilization of a protein to a gold surface through multiple host-guest interactions
Schwarz D, Elgaher W, Hollemeyer K, Hirsch A, Wenz G (2019)
J. Mater. Chem. B, 7 (40): 6148-6155DOI: 10.1039/c9tb00560a
From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds
Elangovan S, Afanasenko A, Haupenthal J, Sun Z, Liu Y, Hirsch A, Barta K (2019)
ACS Cent. Sci., 5 (10): 1707-1716DOI: 10.1021/acscentsci.9b00781
Surface state tunable energy and mass renormalization from homothetic quantum dot arrays
Piquero-Zulaica I, Li J, Abd El-Fattah Z, Solianyk L, Gallardo I, Monjas L, Hirsch A, Arnau A, Ortega J, Stöhr M, Lobo-Checa J (2019)
Nanoscale, 11 (48): 23132-23138DOI: 10.1039/C9NR07365E
2018
Lipid-DNAs as Solubilizers of m THPC
Liu Y, de Vries J, Liu Q, Hartman A, Wieland G, Wieczorek S, Börner H, Wiehe A, Buhler E, Stuart M, …, Herrmann A, Hirsch A (2018)
Chem. Eur. J., 24 (4): 798-802DOI: 10.1002/chem.201705206
Exploration of ligand binding modes towards the identification of compounds targeting HuR: a combined STD-NMR and Molecular Modelling approach
Vasile F, Della Volpe S, Ambrosio F, Costa G, Unver M, Zucal C, Rossi D, Martino E, Provenzani A, Hirsch A, …, Potenza D, Collina S (2018)
Sci Rep, 8 (1)DOI: 10.1038/s41598-018-32084-z
Druggability Assessment of Targets Used in Kinetic Target-Guided Synthesis
Unver M, Gierse R, Ritchie H, Hirsch A (2018)
Journal of medicinal chemistry, 61 (21): 9395-9409DOI: 10.1021/acs.jmedchem.8b00266
Phage Display on the Anti-infective Target 1-Deoxy-d-xylulose-5-phosphate Synthase Leads to an Acceptor-Substrate Competitive Peptidic Inhibitor
Marcozzi A, Masini T, Di Zhu, Pesce D, Illarionov B, Fischer M, Herrmann A, Hirsch A (2018)
Chembiochem : a European journal of chemical biology, 19 (1): 58-65DOI: 10.1002/cbic.201700402
Glucansucrase (mutant) enzymes from Lactobacillus reuteri 180 efficiently transglucosylate Stevia component rebaudioside A, resulting in a superior taste
Te Poele E, Devlamynck T, Jäger M, Gerwig G, van de Walle D, Dewettinck K, Hirsch A, Kamerling J, Soetaert W, Dijkhuizen L (2018)
Sci. Rep., 8 (1)DOI: 10.1038/s41598-018-19622-5
Delivery system for budesonide based on lipid-DNA
Liu Y, Bos I, Oenema T, Meurs H, Maarsingh H, Hirsch A (2018)
Eur J Pharm Biopharm, 130: 123-127DOI: 10.1016/j.ejpb.2018.06.012
Dynamic Proteoids Generated From Dipeptide-Based Monomers
Liu Y, Stuart M, Buhler E, Hirsch A (2018)
Macromolecular rapid communications, 39 (13)DOI: 10.1002/marc.201800099
Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin
Jumde V, Mondal M, Gierse R, Unver M, Magari F, van Lier R, Heine A, Klebe G, Hirsch A (2018)
ChemMedChem, 13 (21): 2266-2270DOI: 10.1002/cmdc.201800446
Donepezil-melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments
Lozinska I, Swierczynska A, Moleda Z, Hartman A, Hirsch A, Czarnocki Z (2018)
Archiv der Pharmazie, 351 (11)DOI: 10.1002/ardp.201800194
2017
Fine-tuning Nanocarriers Specifically toward Cargo: A Competitive Study on Solubilizing Related Photosensitizers for Photodynamic Therapy
Wieczorek S, Remmler D, Masini T, Kochovski Z, Hirsch A, Börner H (2017)
Bioconjugate chemistry, 28 (3): 760-767DOI: 10.1021/acs.bioconjchem.6b00549
Insight into the complete substrate-binding pocket of ThiT by chemical and genetic mutations
Swier L, Monjas L, Reeßing F, Oudshoorn R, Aisyah, Primke T, Bakker M, van Olst E, Ritschel T, Faustino I, …, Hirsch A, Slotboom D (2017)
MedChemComm, 8 (5): 1121-1130DOI: 10.1039/c7md00079k
Saccharide-Containing Dynamic Proteoids
Liu Y, Stuart M, Witte M, Buhler E, Hirsch A (2017)
Chemistry (Weinheim an der Bergstrasse, Germany), 23 (64): 16162-16166DOI: 10.1002/chem.201703584
Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers
Liu Y, Lehn J, Hirsch A (2017)
Accounts of chemical research, 50 (2): 376-386DOI: 10.1021/acs.accounts.6b00594
DXS as a target for structure-based drug design
Gierse R, Redeem E, Diamanti E, Wrenger C, Groves M, Hirsch A (2017)
Future medicinal chemistry, 9 (11): 1277-1294DOI: 10.4155/fmc-2016-0239
Molecular insight into specific 14-3-3 modulators: Inhibitors and stabilisers of protein-protein interactions of 14-3-3
Hartman A, Hirsch A (2017)
European journal of medicinal chemistry, 136: 573-584DOI: 10.1016/j.ejmech.2017.04.058
Compounds Interfering with Embryonic Lethal Abnormal Vision (ELAV) Protein-RNA Complexes: An Avenue for Discovering New Drugs
Nasti R, Rossi D, Amadio M, Pascale A, Unver M, Hirsch A, Collina S (2017)
Journal of medicinal chemistry, 60 (20): 8257-8267DOI: 10.1021/acs.jmedchem.6b01871
Pentapeptide-rich peptidoglycan at the Bacillus subtilis cell-division site
Morales Angeles D, Liu Y, Hartman A, Borisova M, Sousa Borges A, Kok N, Beilharz K, veening j, Mayer C, Hirsch A, Scheffers D (2017)
Molecular microbiology, 104 (2): 319-333DOI: 10.1111/mmi.13629
Bicyclic enol cyclocarbamates inhibit penicillin-binding proteins
Dockerty P, Edens J, Tol M, Morales Angeles D, Domenech A, Liu Y, Hirsch A, veening j, Scheffers D, Witte M (2017)
Org. Biomol. Chem., 15 (4): 894-910DOI: 10.1039/c6ob01664b
Designed Spiroketal Protein Modulation
Scheepstra M, Andrei S, Unver M, Hirsch A, Leysen S, Ottmann C, Brunsveld L, Milroy L (2017)
Angewandte Chemie (International ed. in English), 56 (20): 5480-5484DOI: 10.1002/anie.201612504
Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine
Monjas L, Swier L, Setyawati I, slotboom d, Hirsch A (2017)
ChemMedChem, 12 (20): 1693-1696DOI: 10.1002/cmdc.201700440
2016
Proteoid Dynamers with Tunable Properties
Liu Y, Stuart M, Buhler E, Lehn J, Hirsch A (2016)
Novel Strategies for the Treatment of Pseudomonas aeruginosa Infections
Wagner S, Sommer R, Hinsberger S, Lu C, Hartmann R, Empting M, Titz A (2016)
Journal of medicinal chemistry, 59 (13): 5929-69DOI: 10.1021/acs.jmedchem.5b01698
Design and synthesis of thiamine analogues to study their binding to the ECF transporter for thiamine in bacteria
Monjas L, Swier L, Voogd A, Oudshoorn R, Hirsch A, Slotboom D (2016)
Med. Chem. Commun., 7 (5): 966-971DOI: 10.1039/C6MD00022C
Furoates and thenoates inhibit pyruvate dehydrogenase kinase 2 allosterically by binding to its pyruvate regulatory site
Masini T, Birkaya B, van Dijk S, Mondal M, Hekelaar J, Jäger M, van Terwisscha Scheltinga A, Patel M, Hirsch A, Moman E (2016)
J. Enzyme Inhib. Med. Chem., 31 (sup4): 170-175DOI: 10.1080/14756366.2016.1201812
Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry
Mondal M, Radeva N, Fanlo-Virgós H, Otto S, Klebe G, Hirsch A (2016)
Angewandte Chemie (International ed. in English), 55 (32): 9422-6DOI: 10.1002/anie.201603074
Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin
Mondal M, Unver M, Pal A, Bakker M, Berrier S, Hirsch A (2016)
Chem. Eur. J., 22 (42): 14826-14830DOI: 10.1002/chem.201603001
Discovery of the first small-molecule CsrA-RNA interaction inhibitors using biophysical screening technologies
Maurer C, Fruth M, Empting M, Avrutina O, Hossmann J, Nadmid S, Gorges J, Herrmann J, Kazmaier U, Dersch P, Müller R, Hartmann R (2016)
Future Med. Chem., 8 (9): 931-47DOI: 10.4155/fmc-2016-0033
Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors
Elgaher W, Sharma K, Haupenthal J, Saladini F, Pires M, Real E, Mely Y, Hartmann R (2016)
Journal of medicinal chemistryDOI: 10.1021/acs.jmedchem.6b00730
Application of Dual Inhibition Concept within Looped Autoregulatory Systems toward Antivirulence Agents against Pseudomonas aeruginosa Infections
Thomann A, de Mello Martins, Antonio G G, Brengel C, Empting M, Hartmann R (2016)
ACS chemical biologyDOI: 10.1021/acschembio.6b00117
Dissecting the Multiple Roles of PqsE in Pseudomonas aeruginosa Virulence by Discovery of Small Tool Compounds
Zender M, Witzgall F, Drees S, Weidel E, Maurer C, Fetzner S, Blankenfeldt W, Empting M, Hartmann R (2016)
ACS chemical biologyDOI: 10.1021/acschembio.6b00156
2015
Combinatorial screening for specific drug solubilizers with switchable release profiles
Wieczorek S, Vigne S, Masini T, Ponader D, Hartmann L, Hirsch A, Börner H (2015)
Macromolecular Bioscience, 15 (1): 82-9DOI: 10.1002/mabi.201400443
New PqsR Inverse Agonists
Schütz C (2015)
Patent (EP 20150104.6-1110)
Novel PqsR Inverse Agonists
Hahmad M (2015)
Patent (EP 201523196)
Dynamic combinatorial chemistry: a tool to facilitate the identification of inhibitors for protein targets
Mondal M, Hirsch A (2015)
Chem. Soc. Rev., 44 (8): 2455-88DOI: 10.1039/c4cs00493k
Fighting malaria: structure-guided discovery of nonpeptidomimetic plasmepsin inhibitors
Huizing A, Mondal M, Hirsch A (2015)
Journal of medicinal chemistry, 58 (13): 5151-63DOI: 10.1021/jm5014133
Harnessing dynamic combinatorial chemistry in the search for new ligands for protein targets
Monjas L, Hirsch A (2015)
Future medicinal chemistry, 7 (16): 2095-8DOI: 10.4155/fmc.15.146
Structure-based design of potent small-molecule binders to the S-component of the ECF transporter for thiamine
Swier L, Monjas L, Guskov A, Voogd A, Erkens G, slotboom d, Hirsch A (2015)
Chembiochem : a European journal of chemical biology, 16 (5): 819-26DOI: 10.1002/cbic.201402673
Fragment growing exploiting dynamic combinatorial chemistry of inhibitors of the aspartic protease endothiapepsin
Mondal M, Groothuis D, Hirsch A (2015)
Med. Chem. Commun., 6 (7): 1267-1271DOI: 10.1039/C5MD00157A
Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin
Hartman A, Mondal M, Radeva N, Klebe G, Hirsch A (2015)
International journal of molecular sciences, 16 (8): 19184-94DOI: 10.3390/ijms160819184
Supramolecular chemistry … and beyond
Hirsch A (2015)
Angewandte Chemie (International ed. in English), 54 (38): 11013-4DOI: 10.1002/anie.201506536
Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS
Masini T, Lacy B, Monjas L, Hawksley D, Voogd A, Illarionov B, Iqbal A, Leeper F, Fischer M, Kontoyianni M, Hirsch A (2015)
Org. Biomol. Chem., 13 (46): 11263-77DOI: 10.1039/c5ob01666e
Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa
Sahner J, Empting M, Kamal A, Weidel E, Groh M, Börger C, Hartmann R (2015)
European journal of medicinal chemistry, 96: 14-21DOI: 10.1016/j.ejmech.2015.04.007
Advanced mutasynthesis studies on the natural α-pyrone antibiotic myxopyronin from Myxococcus fulvus
Sahner J, Sucipto H, Wenzel S, Groh M, Hartmann R, Müller R (2015)
ChemBioChem, 16: 946-953DOI: 10.1002/cbic.201402666
2014
A natural-product switch for a dynamic protein interface
Scheepstra M, Nieto L, Hirsch A, Fuchs S, Leysen S, Lam C, het Panhuis L, van Boeckel C, Wienk H, Boelens R, …, Milroy L, Brunsveld L (2014)
Angewandte Chemie (International ed. in English), 53 (25): 6443-8DOI: 10.1002/anie.201403773
A doubly hermaphroditic chiral crown ether
Hirsch A, Sirlin C, Harrowfield J, Lehn J (2014)
DOI: 10.1039/C4CE00879K
Development of inhibitors of the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway enzymes as potential anti-infective agents
Masini T, Hirsch A (2014)
Journal of medicinal chemistry, 57 (23): 9740-63DOI: 10.1021/jm5010978
Theoretical and structural analysis of long C-C bonds in the adducts of polycyanoethylene and anthracene derivatives and their connection to the reversibility of Diels-Alder reactions
Hirsch A, Reutenauer P, Le Moignan M, Ulrich S, Boul P, Harrowfield J, Jarowski P, Lehn J (2014)
Chem. Eur. J., 20 (4): 1073-80DOI: 10.1002/chem.201303276
Structure-based design of inhibitors of the aspartic protease endothiapepsin by exploiting dynamic combinatorial chemistry
Mondal M, Radeva N, Köster H, Park A, Potamitis C, Zervou M, Klebe G, Hirsch A (2014)
Angewandte Chemie (International ed. in English), 53 (12): 3259-63DOI: 10.1002/anie.201309682
De novo fragment-based design of inhibitors of DXS guided by spin-diffusion-based NMR spectroscopy
Masini T, Pilger J, Kroezen B, Illarionov B, Lottmann P, Fischer M, Griesinger C, Hirsch A (2014)
Chemical Science, 5 (9): 3543-3551DOI: 10.1039/C4SC00588K
Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections
Hinsberger S, Jong J, Groh M, Haupenthal J, Hartmann R (2014)
European journal of medicinal chemistry, 76: 343-51DOI: 10.1016/j.ejmech.2014.02.014
From in vitro to in cellulo: structure-activity relationship of (2-nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa
Storz M, Allegretta G, Kirsch B, Empting M, Hartmann R (2014)
Organic & biomolecular chemistry, 12 (32): 6094-104DOI: 10.1039/c4ob00707g
Overcoming the unexpected functional inversion of a PqsR antagonist in Pseudomonas aeruginosa: an in vivo potent antivirulence agent targeting pqs quorum sensing
Lu C, Maurer C, Kirsch B, Steinbach A, Hartmann R (2014)
Angewandte Chemie (International ed. in English), 53 (4): 1109-12DOI: 10.1002/anie.201307547
2013
Druggability of the enzymes of the non-mevalonate-pathway
Masini T, Kroezen B, Hirsch A (2013)
Drug Discov. Today, 18 (23-24): 1256-62DOI: 10.1016/j.drudis.2013.07.003
Total synthesis, stereochemical elucidation and biological evaluation of Ac 2 SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis
Geerdink D, Horst B, Lepore M, Mori L, Puzo G, Hirsch A, Gilleron M, Libero G, Minnaard A (2013)
Chemical Science, 4 (2): 709-716DOI: 10.1039/C2SC21620E
Imidazole- and Benzimidazole-Based Inhibitors of the Kinase IspE: Targeting the Substrate-Binding Site and the Triphosphate-Binding Loop of the ATP Site
Mombelli P, Le Chapelain C, Munzinger N, Joliat E, Illarionov B, Schweizer W, Hirsch A, Fischer M, Bacher A, Diederich F (2013)
Eur. J. Org. Chem., 2013 (6): 1068-1079DOI: 10.1002/ejoc.201201467
Exploiting specific interactions toward next-generation polymeric drug transporters
Wieczorek S, Krause E, Hackbarth S, Röder B, Hirsch A, Börner H (2013)
J. Am. Chem. Soc., 135 (5): 1711-4DOI: 10.1021/ja311895z
2012
Metal-ion-induced shape switching: Stereoselective formation of a dinuclear Hg(II) double helicate from a hydrazonobis(acylhydrazone) ligand
Schaeffer G, Harrowfield J, Lehn J, Hirsch A (2012)
The isoprenoid-precursor dependence of Plasmodium spp
van der Meer J, Hirsch A (2012)
Nat. Prod. Rep., 29 (7): 721-8DOI: 10.1039/c2np20013a
Biodynamers: self-organization-driven formation of doubly dynamic proteoids
Hirsch A, Buhler E, Lehn J (2012)
J. Am. Chem. Soc., 134 (9): 4177-83DOI: 10.1021/ja2099134
Exploring the Ribose Sub-Pocket of the Substrate-Binding Site in Escherichia coli IspE: Structure-Based Design, Synthesis, and Biological Evaluation of Cytosines and Cytosine Analogues
Schütz A, Osawa S, Mathis J, Hirsch A, Bernet B, Illarionov B, Fischer M, Bacher A, Diederich F (2012)
Eur. J. Org. Chem., 2012 (17): 3278-3287DOI: 10.1002/ejoc.201200296
Total synthesis of (-)-doliculide, structure-activity relationship studies and its binding to F-actin
Matcha K, Madduri A, Roy S, Ziegler S, Waldmann H, Hirsch A, Minnaard A (2012)
Chembiochem : a European journal of chemical biology, 13 (17): 2537-48DOI: 10.1002/cbic.201200512
2010
Bioconjugates to specifically render inhibitorswater-soluble
Hirsch A, Diederich F, Antonietti M, Börner H (2010)
Soft Matter, 6 (1): 88-91DOI: 10.1039/B915928B
2008
Synthesis and characterization of cytidine derivatives that inhibit the kinase IspE of the non-mevalonate pathway for isoprenoid biosynthesis
Crane C, Hirsch A, Alphey M, Sgraja T, Lauw S, Illarionova V, Rohdich F, Eisenreich W, Hunter W, Bacher A, Diederich F (2008)
ChemMedChem, 3 (1): 91-101DOI: 10.1002/cmdc.200700208
The Non-Mevalonate Pathway to Isoprenoid Biosynthesis: A Potential Source of New Drug Targets
Hirsch A, Diederich F (2008)
Chimia, 62 (4): 226-230DOI: 10.2533/chimia.2008.226
Inhibitors of the kinase IspE: structure-activity relationships and co-crystal structure analysis
Hirsch A, Alphey M, Lauw S, Seet M, Barandun L, Eisenreich W, Rohdich F, Hunter W, Bacher A, Diederich F (2008)
Organic & biomolecular chemistry, 6 (15): 2719-30DOI: 10.1039/b804375b
2007
Phosphate recognition in structural biology
Hirsch A, Fischer F, Diederich F (2007)
Angew. Chem. Int. Ed., 46 (3): 338-52DOI: 10.1002/anie.200603420
Nonphosphate inhibitors of IspE protein, a kinase in the non-mevalonate pathway for isoprenoid biosynthesis and a potential target for antimalarial therapy
Hirsch A, Lauw S, Gersbach P, Schweizer W, Rohdich F, Eisenreich W, Bacher A, Diederich F (2007)
ChemMedChem, 2 (6): 806-10DOI: 10.1002/cmdc.200700014
2006
Double conjugate addition of dithiols to propargylic carbonyl systems to generate protected 1,3-dicarbonyl compounds
Sneddon H, van den Heuvel A, Hirsch A, Booth R, Shaw D, Gaunt M, Ley S (2006)
The Journal of organic chemistry, 71 (7): 2715-25DOI: 10.1021/jo052514s