Anthony K Mittermaier

Anthony K Mittermaier
McGill University | McGill · Department of Chemistry

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104
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Introduction
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Publications

Publications (104)
Article
We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP),...
Article
Supramolecular chemistry involves the noncovalent assembly of monomers into materials with unique properties and wide-ranging applications. Thermal analysis is a key analytical tool in this field, as it provides quantitative thermodynamic information on both the structural stability and nature of the underlying molecular interactions. However, ther...
Article
Full-text available
Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro (main coronaviruses cysteine-protease) has been...
Preprint
Full-text available
Supramolecular chemistry involves the non-covalent assembly of monomers into materials with unique properties and wide-ranging applications. Thermal analysis is a key analytical tool in this field, as it provides quantitative thermodynamic information on both the structural stability and nature of the underlying molecular interactions. However ther...
Preprint
Supramolecular chemistry involves the non-covalent assembly of monomers into materials with unique properties and wide-ranging applications. Thermal analysis is a key analytical tool in this field, as it provides quantitative thermodynamic information on both the structural stability and nature of the underlying molecular interactions. However ther...
Preprint
Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for...
Preprint
Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for...
Article
Kinases play central roles in many cellular processes, transferring the terminal phosphate groups of nucleoside triphosphates (NTPs) onto substrates. In the absence of substrates, kinases can also hydrolyse NTPs producing NDPs and inorganic phosphate. Hydrolysis is usually much less efficient than the native phosphoryl transfer reaction. This may b...
Preprint
Full-text available
We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP),...
Preprint
We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP),...
Preprint
Full-text available
Supramolecular chemistry involves the non-covalent assembly of monomers into materials with unique properties and wide-ranging applications. Thermal analysis is a key analytical tool in this field, as it provides quantitative thermodynamic information on both the structural stability and nature of the underlying molecular interactions. However ther...
Preprint
Supramolecular chemistry involves the non-covalent assembly of monomers into materials with unique properties and wide-ranging applications. Thermal analysis is a key analytical tool in this field, as it provides quantitative thermodynamic information on both the structural stability and nature of the underlying molecular interactions. However ther...
Article
Full-text available
The last 5 years have seen a series of advances in the application of isothermal titration microcalorimetry (ITC) and interpretation of ITC data. ITC has played an invaluable role in understanding multiprotein complex formation including proteolysis‐targeting chimeras (PROTACS), and mitochondrial autophagy receptor Nix interaction with LC3 and GABA...
Article
Full-text available
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. SARS-CoV-2 infection is necessary but not sufficient for development of clinical COVID-19 disease. Currently, there are no approved pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest...
Article
Full-text available
Human chromosomes terminate in long, single-stranded, DNA overhangs of the repetitive sequence (TTAGGG)n. Sets of four adjacent TTAGGG repeats can fold into guanine quadruplexes (GQ), four-stranded structures that are implicated in telomere maintenance and cell immortalization and are targets in cancer therapy. Isolated GQs have been studied in det...
Article
Full-text available
G-quadruplexes (G4s) are four-stranded, guanine-rich nucleic acid structures that can influence a variety of biological processes such as the transcription and translation of genes and DNA replication. In many cases, a single G4-forming nucleic acid sequence can adopt multiple different folded conformations that interconvert on biologically relevan...
Article
Full-text available
Isothermal titration calorimetry (ITC) involves accurately measuring the heat that is released or absorbed in real time when one solution is titrated into another. This technique is usually used to measure the thermodynamics of binding reactions. However, there is mounting interest in using it to measure reaction kinetics, particularly enzymatic ca...
Preprint
Full-text available
Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro has been identified as a promising target for t...
Chapter
Electrostatic interactions in intrinsically disordered proteins (IDPs) and regions (IDRs) can strongly influence their conformational sampling. Side chain pKa values provide information on the electrostatic interaction energies of individual side chains and are required to accurately determine the molecular net charge and charge distribution. Nucle...
Preprint
Full-text available
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selectio...
Preprint
Full-text available
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selectio...
Preprint
Full-text available
SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selectio...
Article
The self‐immolative, amplified release of small molecules, in response to a nucleic‐acid signal, from 1D, 2D, and 3D assemblies using the hybridization chain reaction (HCR) is demonstrated. These assemblies effectively separate the reactive groups, enabling the release of small molecules in response to a biomarker of interest, and could find applic...
Article
Triggering the release of small molecules in response to unique biomarkers is important for applications in drug delivery and biodetection. Due to typically low quantities of biomarker, amplifying release is necessary to gain appreciable responses. Nucleic acids have been used for both their biomarker recognition properties and as stimuli, notably...
Article
The 300-kDa ClpP1P2 protease from Mycobacterium tuberculosis collaborates with the AAA+ (ATPases associated with a variety of cellular activities) unfoldases, ClpC1 and ClpX, to degrade substrate proteins. Unlike in other bacteria, all of the components of the Clp system are essential for growth and virulence of mycobacteria, and their inhibitors s...
Preprint
Full-text available
The 300-kDa ClpP1P2 protease from Mycobacterium tuberculosis collaborates with the AAA+ (ATPases associated with a variety of cellular activities) unfoldases, ClpC1 and ClpX, to degrade substrate proteins. Unlike in other bacteria, all the components of the Clp system are essential for growth and virulence of mycobacteria, and their inhibitors show...
Article
The complex folding energy landscape of DNA G-quadruplexes leads to numerous conformations for this functionally important class of non-canonical DNA structures. A new layer of conformational heterogeneity comes from sequences with different numbers of G-nucleotides in each of the DNA G-strands that form the four-stranded G-quartet core. The mechan...
Article
Over the past decade, many drug discovery endeavors have been invested in targeting the serine proteases prolyl oligopeptidase (POP) for the treatment of Alzheimer's and Parkinson's disease and, more recently, epithelial cancers. Our research group has focused on the discovery of reversible covalent inhibitors, namely nitriles, to target the cataly...
Article
Kinases are widely distributed in nature and are implicated in many human diseases, thus an understanding of their activity and regulation is of fundamental importance. Several kinases are known to be inhibited by ADP, however thorough investigation of this phenomenon is hampered by the lack of a simple and effective assay for studying this inhibit...
Article
Over the past decade, there has been an increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity towards elect...
Article
The carbapenem-hydrolyzing Class D β-lactamase OXA-143 was isolated in Brazil in 2004. The D224A variant, known as OXA-231, was described in 2012 as exhibiting less activity towards imipenem and increased oxacillinase activity. Additionally, the P227S mutation was reported as a case of convergent evolution for homologous enzymes. To investigate the...
Article
Intramolecular electrostatic attraction and repulsion strongly influence the conformational sampling of intrinsically disordered proteins and domains (IDPs). In order to better understand this complex relationship, we have used nuclear magnetic resonance to measure side‐chain pKa values and pH‐dependent translational diffusion coefficients for the...
Article
Full-text available
Understanding how biological macromolecules assemble into higher-order structures is critical to explaining their function in living organisms and engineered biomaterials. Transient, partly-structured intermediates are essential in many assembly processes and pathway selection, but are challenging to characterize. Here we present a simple thermal h...
Article
Techniques for rapidly measuring both the strength and mode of enzyme inhibitors are crucial to lead generation and optimization in drug development. Isothermal titration calorimetry (ITC) is emerging as a powerful tool for measuring enzyme kinetics with distinct advantages over traditional techniques. ITC measures heat flow, a feature of nearly al...
Article
Full-text available
Intracellular deposits of α‐synuclein in the form of Lewy bodies are major hallmarks of Parkinson's disease (PD) and a range of related neurodegenerative disorders. Post‐translational modifications (PTMs) of α‐synuclein are increasingly thought to be major modulators of its structure, function, degradation and toxicity. Among these PTMs, phosphoryl...
Article
Full-text available
Although drug development typically focuses on binding thermodynamics, recent studies suggest that kinetic properties can strongly impact a drug candidate's efficacy. Robust techniques for measuring inhibitor association and dissociation rates are therefore essential. To address this need, we have developed a pair of complementary isothermal titrat...
Article
Differential scanning calorimetry (DSC) is a powerful technique for quantifying thermodynamic parameters governing biomolecular folding and binding interactions. This information is critical in the design of new pharmaceutical compounds. However, many pharmaceutically relevant ligands are chemically unstable at the high temperatures used in DSC ana...
Article
Tubulins are an ancient family of eukaryotic proteins characterized by an amino-terminal globular domain and disordered carboxyl terminus. These carboxyl termini play important roles in modulating the behavior of microtubules in living cells. However, the atomic-level basis of their function is not well understood. These regions contain multiple ac...
Article
We present a rapid and efficient method to generate a family of platinum supramolecular square complexes, including previously inaccessible targets, through the use of ball milling mechanochemistry. This one-pot, two-step process occurs in minutes and enables the synthesis of the squares [Pt4(en)4(N∩N)4][CF3SO3]8 (en= ethylenediamine, N∩N = 4,4’-bi...
Article
Isothermal titration calorimetry (ITC) is a powerful tool for acquiring both thermodynamic and kinetic data for biological interactions including molecular recognition and enzymatic catalysis. ITC-based kinetics measurements typically focus on reactions taking place over long timescales (tens of minutes or hours) in order to avoid complications due...
Article
In the history of therapeutics, covalent drugs occupy a very distinct category. While representing a significant fraction of the drugs on the market, very few have been deliberately designed to interact covalently with their biological target. In this review, the prevalence of covalent drugs will first be briefly covered, followed by an introductio...
Article
G-quadruplexes (GQs) are four-stranded nucleic acid secondary structures formed by guanosine (G)-rich DNA and RNA sequences. It is becoming increasingly clear that cellular processes including gene expression and mRNA translation are regulated by GQs. GQ structures have been extensively characterized, however little attention to date has been paid...
Article
Differential scanning calorimetry (DSC) is a powerful technique for measuring tight biomolecular interactions. However, many pharmaceutically relevant ligands are chemically unstable at the high temperatures used in DSC analyses. Thus, measuring binding interactions is challenging because the concentrations of ligands and thermally-converted produc...
Article
Differential scanning calorimetry (DSC) is a powerful technique for measuring tight biomolecular interactions. However, many pharmaceutically relevant ligands are chemically unstable at the high temperatures used in DSC analyses. Thus, measuring binding interactions is challenging because the concentrations of ligands and thermally-converted produc...
Article
Full-text available
i-Motifs are four-stranded DNA structures consisting of two parallel DNA duplexes held together by hemi-protonated and intercalated cytosine base pairs (C:CH+). They have attracted considerable research interest for their potential role in gene regulation and their use as pH responsive switches and building blocks in macromolecular assemblies. At n...
Article
Full-text available
G-quadruplexes (GQs) are 4-stranded DNA structures formed by tracts of stacked, Hoogsteen-hydrogen bonded guanosines. GQs are found in gene promoters and telomeres where they regulate gene transcription and telomere elongation. Though GQ structures are well-characterized, many aspects of their conformational dynamics are poorly understood. For exam...
Article
Bicyclic chiral scaffolds are privileged motifs in medicinal chemistry. Over the years, we have reported covalent bicyclic prolyl oligopeptidase inhibitors that were highly selective for POP over a number of homologous proteins. Herein we wish to report the structure-based design and synthesis of a novel class of POP inhibitors based on hexahydrois...
Article
Full-text available
Deletion of F508 (F508del) in the first nucleotide binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) results in destabilization of the domain, intramolecular interactions involving the domain and the entire channel. The destabilization caused by F508del manifests itself in defective channel processing and chann...
Article
Allosteric transmission of information between distant sites in biological macromolecules often involves collective transitions between active and inactive conformations. Nuclear magnetic resonance (NMR) spectroscopy can yield detailed information on these dynamics. In particular, relaxation dispersion techniques provide structural, dynamic, and me...
Article
Biotechnological applications of enzymes can involve the use of these molecules under non-physiological conditions. Thus it is of interest to understand how environmental variables affect protein structure and dynamics and how this ultimately modulates enzyme function. NADH oxidase (NOX) from Thermus thermophilus exemplifies how enzyme activity can...
Article
Little is currently known about the molecular determinants of energy barriers along enzyme catalytic pathways. Kern and co-workers have studied this question in adenylate kinase (Adk) and now reveal that a single Mg2+ ion can accelerate two distinct steps, thus uncovering an unexpected dual role for this ubiquitous cofactor.
Article
Allostery is a nearly ubiquitous feature of biological systems in which ligand binding or covalent modification at one site alters the activities of distant sites in a macromolecule or macromolecular complex. The molecular mechanisms underlying this phenomenon have been studied for decades. Nevertheless there are many aspects that remain poorly und...
Article
Enzyme activity is commonly controlled by allostery, where ligand binding at one site alters the activities of distant sites. Classical explanations for multisubunit proteins involve conformational transitions that are fundamentally deterministic. For example, in the Monod-Wyman-Changeaux (MWC) paradigm, conformational transitions occur simultaneou...
Article
Full-text available
Much of our knowledge of protein binding pathways is derived from extremely stable complexes that interact very tightly, with lifetimes of hours to days. Much less is known about weaker interactions and transient complexes, since these are challenging to characterize experimentally. Nevertheless, these types of interactions are ubiquitous in living...
Article
The Baeyer-Villiger monooxygenases (BVMOs) are a group of bacterial enzymes that are able to catalyze the synthetically useful Baeyer-Villiger oxidation reaction. As such, these enzymes have attracted considerable attention as potential industrial biocatalysts. The interest in these enzymes has led to a desire to be able to rationally design them f...
Article
A series of three platinum(II) phenanthroimidazoles each containing a protonable side-chain appended from the phenyl moiety through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) were evaluated for their capacities to bind to human telomere, c-Myc, and c-Kit derived G-quadruplexes. The side-chain has been optimized to enable a multivalent b...
Article
Nuclear magnetic resonance (NMR) spectroscopy can provide detailed information on protein-ligand interactions that is inaccessible using other biophysical techniques. This chapter focuses on NMR-based approaches for extracting affinity and rate constants for weakly binding transient protein complexes with lifetimes of less than about a second. Seve...
Article
Full-text available
G-quadruplexes (noncanonical secondary structures), have gained recognition as viable targets for chemotherapeutic drug design based on their ability to interfere with cancer cell proliferation. These DNA structures, held together by Hoogsteen hydrogen bonds, result from the folding of guanine (G)-rich DNA sequences in the presence of potassium or...
Article
NMR Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion experiments represent a powerful approach for characterizing protein internal motions and for gaining insight into fundamental biological processes such as protein folding, catalysis, and allostery. In most cases, CPMG data are analyzed assuming that the protein exchanges between two differ...
Article
Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibi...
Article
Isothermal titration calorimetry (ITC) can provide detailed information on the thermodynamics of biomolecular interactions in the form of equilibrium constants, KA, and enthalpy changes, ΔHA. A powerful application of this technique involves analyzing the temperature dependences of ITC-derived KA and ΔHA values to gain insight into thermodynamic li...
Article
A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere-derived intramolecular G-quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G-quadruplexes from sequences...
Article
We have characterized the backbone dynamics of NADH oxidase from Thermus thermophilus (NOX) using a recently-developed suite of NMR experiments designed to isolate exchange broadening, together with 15N R 1, R 1ρ , and {1H}-15N steady-state NOE relaxation measurements performed at 11.7 and 18.8 T. NOX is a 54 kDa homodimeric enzyme that belongs to...