Anthony Mittermaier

Protocol for detecting in vitro riboswitch conformational switching using a fluorescence anisotropy single-stranded RNA-targeting approach

Amanda Clairoux, Maira Rivera, Maureen McKeague, Anthony Mittermaier

We present a high-sensitivity fluorescence anisotropy-based protocol (fluorescence anisotropy single-stranded targeting [FASST]) to monitor in vitro ligand-induced conformational switching of riboswitches. We first describe the sequence design of single-stranded fluorescent DNA probes that selectively bind to specific riboswitch conformational states. Next, we …

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Integration of computational and experimental techniques for the discovery of PLpro covalent inhibitors. When large virtual screening and rational design meet

Ho Ying Huang, Sharon Pinus, Xiaocong Zhang, Guanyu Wang et autres

Papain-like protease (PL pro ) and 3-chymotrypsin-like protease (3CL pro or Mpro) are viral enzymes essential for the replication of SARS-CoV-2, the virus causing coronavirus disease of 2019 (COVID-19) infection. While 3CL pro has been the main target of many potential antivirals …

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Integration of Computational and Experimental Techniques for the Discovery of SARS-CoV-2 PLpro Covalent Inhibitors

Ho Ying Huang, Sharon Pinus, Xiao Cong Zhang, Guanyu Wang et autres

Papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro or Mpro) are viral enzymes essential for the replication of SARS-CoV-2, the virus causing COVID-19 infection. While 3CLpro has been the main target of many potential antivirals including nirmatrelvir (active ingredient of Paxlovid), PLpro has …

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Contributors

Olga Abián, Shahbaz Ahmed, Chad A. Brautigam, Karl Brillet et autres

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Design, synthesis and biological evaluation of novel [5,5]-fused thiazolidine/oxazolidine inhibitors for targeting prolyl oligopeptidase

Thershan Satkunarajah, Stéphane De Cesco, Ho Ying Huang, Emmanuelle Nguyen et autres

In the course of developing prolyl oligopeptidase (POP) inhibitors, our group has synthesized different series of inhibitors ranging from chiral bicyclic scaffolds to peptidomimetics, the design of which has been a product of in silico derived high-throughput screening followed by docking-guided optimization. …

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Effects of flanking regions on DNA i-motif folding and stability

Chuyang Zhang, Hariz Nizal, Christopher Hennecker, Anthony Mittermaier

i-Motifs (iMs) are four-stranded non-canonical nucleic acid secondary structures that are formed by cytosine-rich sequences. Putative iM-forming sequences are concentrated in human promoter and telomeric regions, suggesting possible biological roles. However, many iMs do not readily fold at neutral pH, sparking interest …

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Inhibitor‐induced dimerization mediates lufotrelvir resistance in mutants of SARS ‐ CoV ‐2 3C‐like protease

Guanyu Wang, Felipe Venegas, Andrés M. Rueda, Osvaldo Yáñez et autres

Abstract The emergence of SARS‐CoV‐2 and other lethal coronaviruses has prompted extensive research into targeted antiviral treatments, particularly focusing on the viral 3C‐like protease (3CLpro) due to its essential role for viral replication. However, the rise of drug resistance mutations poses threats …

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Mechanistic Characterization of Covalent Enzyme Inhibition by Isothermal Titration Calorimetry Kinetic Competition (ITC-KC)

Christopher Hennecker, Felipe Venegas, Guanyu Wang, Julia Stille et autres

Covalent enzyme inhibitors can offer high potency and specificity and are increasingly sought after in drug discovery. They typically inhibit in two steps: noncovalent binding followed by covalent bond formation. Rational optimization requires quantitative information on both steps. Current methods for measuring …

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pH-Sulfate Synergy Regulates Processing and Mechanics of Mussel Byssus Protein Condensates

Hamideh R. Alanagh, Magda G. Sánchez-Sánchez, Michael R. Wozny, Yeganeh Habibi et autres

Fluid protein condensates are used as precursor phases for fabricating extracellular protein-based materials, including elastin, spider silk, and mussel byssus. The byssus, used by mussels for anchoring in marine environments, consists of tough, self-healing adhesive fibers. Byssus formation involves the secretion of …

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Structure-Based Optimization and Biological Evaluation of SARS-CoV-2 3CLpro Covalent Inhibitors

Guanyu Wang, Julia Stille, Richard Boulon, Christopher Hennecker et autres

The global emergence of COVID-19, caused by SARS-CoV-2, has underscored the critical need for effective antivirals against coronaviruses. The 3-chymotrypsin-like protease (3CLpro) of coronavirus has been a primary target for drug development due to its critical role across various coronaviruses. Following our …

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pH-sulfate synergy regulates processing and mechanics of mussel byssus protein condensates

Hamideh R. Alanagh, Magda G. Sánchez-Sánchez, Michael R. Wozny, Yeganeh Habibi et autres

Fluid protein condensates are used as precursor phases for fabricating extracellular protein-based materials including elastin, spider silk, and mussel byssus. The byssus, utilized by mussels for anchoring in marine environments, consists of tough, self-healing adhesive fibers. Byssus formation involves the secretion of …

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Docking-based Virtual Screening for the Discovery of RNA-targeting Molecules: Identification of Selective Riboswitch Binding Ligands

Julia Stille, Nathania A. Takyi, Omma S Ayon, Maira Rivera et autres

We present herein one of the very first applications of molecular docking towards the discovery of novel RNA-targeting molecules. Our in-house docking program FITTED was used to perform independ-ent virtual screening campaigns against the TPP, SAM, and FMN riboswitches. Based on the …

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