Bradley T. Falk

Perspectives on Nuclear Magnetic Resonance Spectroscopy in Drug Discovery Research

Janet Caceres‐Cortes, Bradley T. Falk, Luciano Mueller, T. G. Murali Dhar

The drug discovery landscape has undergone a significant transformation over the past decade, owing to research endeavors in a wide range of areas leading to strategies for pursuing new drug targets and the emergence of novel drug modalities. NMR spectroscopy has been …

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Ranking mAb–excipient interactions in biologics formulations by NMR spectroscopy and computational approaches

Chun‐Ting Zhang, Steven T. Gossert, Jonathan S. Williams, Michael J. Little et autres

Excipients are added to biopharmaceutical formulations to enhance protein stability and enable the development of robust formulations with acceptable physicochemical properties, but the mechanism by which they confer stability is not fully understood. Here, we aimed to elucidate the mechanism through direct …

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Investigating protein–excipient interactions of a multivalent V HH therapeutic protein using NMR spectroscopy

Jainik P. Panchal, Bradley T. Falk, Valentyn Antochshuk, Mark A. McCoy

Multispecific therapeutic proteins come in a variety of formats, including bi- and tri-specific antibodies, dual-variable domain antibodies, and CrossMabs. These multivalent proteins are engineered to interact with multiple therapeutic target proteins with high specificity. Multi-domain proteins can be created by linking together …

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Molecular Mechanism of Antimicrobial Excipient-Induced Aggregation in Parenteral Formulations of Peptide Therapeutics

Mingyue Li, Bradley T. Falk, Xingyu Lu, Ryan V. Schroder et autres

Antimicrobial preservatives are used as functional excipients in multidose formulations of biological therapeutics to destroy or inhibit the growth of microbial contaminants, which may be introduced by repeatedly administering doses. Antimicrobial agents can also induce the biophysical instability of proteins and peptides, …

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Identification and characterization of TYK2 pseudokinase domain stabilizers that allosterically inhibit TYK2 signaling

Gregory A. Locke, J.K. Muckelbauer, John S. Tokarski, Christopher M. Barbieri et autres

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Bacterial Thymidylate Synthase Binds Two Molecules of Substrate and Cofactor without Cooperativity

Andrew L. Lee, Paul J. Sapienza, Bradley T. Falk

Thymidylate synthase (TSase) is a clinically important enzyme because it catalyzes synthesis of the sole de novo source of deoxy-thymidylate. Without this enzyme, cells die a “thymineless death” since they are starved of a crucial DNA synthesis precursor. As a drug target, …

Chemical shift imprint of intersubunit communication in a symmetric homodimer

Andrew L. Lee, Bradley T. Falk, Paul J. Sapienza

Regulatory signals between protein subunits depend on communication between sequential binding events. How such long-range communication, or allostery, operates at the subdomain level has been elusive, especially for homooligomeric proteins. To address this problem, homodimers of thymidylate synthase were generated for optimized …

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Profiling Insulin Oligomeric States by 1H NMR Spectroscopy for Formulation Development of Ultra-Rapid-Acting Insulin

Bradley T. Falk, Yingkai Liang, Mark A. McCoy

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Probing subunit communication via a singly ligated state of dimeric thymidylate synthase

Bradley T. Falk

Enzymes are highly dynamic molecules that undergo motions on a wide variety of timescales that are linked to all aspects of their function from mediating substrate binding and enabling chemistry to facilitating regulation by effector ligands. NMR studies on a handful of …

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Inter-Active Site Communication Mediated by the Dimer Interface β-Sheet in the Half-the-Sites Enzyme, Thymidylate Synthase

Paul J. Sapienza, Konstantin I. Popov, David D. Mowrey, Bradley T. Falk et autres

Thymidylate synthase (TS) is a dimeric enzyme conserved in all life forms that exhibits the allosteric feature of half-the-sites activity. Neither the reason for nor the mechanism of this phenomenon is understood. We used a combined nuclear magnetic resonance (NMR) and molecular …

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NMR Assessment of Therapeutic Peptides and Proteins: Correlations That Reveal Interactions and Motions

Bradley T. Falk, Yingkai Liang, Marc Andre Bailly, Fahimeh Raoufi et autres

Abstract NMR measurements of rotational and translational diffusion are used to characterize the solution behavior of a wide variety of therapeutic proteins and peptides. The timescales of motions sampled in these experiments reveal complicated intrinsic solution behavior such as flexibility, that is …

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Cover Feature: Diffusion Profiling of Therapeutic Proteins by Using Solution NMR Spectroscopy (ChemBioChem 7/2019)

Bradley T. Falk, Yingkai Liang, Mark A. McCoy

The cover feature picture shows the use of NMR diffusion measurements to get a closer look at the solution behavior of proteins. A protein′s size can be determined from its movement through a magnetic field gradient. These diffusion spectra can be interpreted …

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