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Pharmacological brake-release of mRNA translation enhances cognitive memory
TLDR
A small molecule is identified, named ISRIB, that potently reverses the effects of eIF2α phosphorylation and promises to contribute to the understanding and treatment of cognitive disorders. Expand
Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response
TLDR
By modulating eIF2B function, ISRIB promises to be an invaluable tool in proof-of-principle studies aiming to ameliorate cognitive defects resulting from neurodegenerative diseases. Expand
Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch
TLDR
Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings, and enables pharmacological modulation all three UPR branches either singly or in combination. Expand
USP7 small-molecule inhibitors interfere with ubiquitin binding
TLDR
Engineering compounds that inhibit USP7 activity by attenuating ubiquitin binding suggests opportunities for developing other deubiquitinase inhibitors and may be a strategy more broadly applicable to inhibiting proteins that require ubiquit in binding for full functional activity. Expand
Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6
TLDR
The discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class is reported. Expand
A Hydrogel-Microsphere Drug Delivery System That Supports Once-Monthly Administration of a GLP-1 Receptor Agonist.
TLDR
Pharmacokinetic simulations indicate that the delivery system should serve well as a once-monthly GLP-1R agonist for treatment of type 2 diabetes in humans. Expand
Broad-Spectrum Allosteric Inhibition of Herpesvirus Proteases
TLDR
A prototypical chemical scaffold for broad-spectrum allosteric inhibition of human herpesvirus proteases is revealed and an approach for the identification of small molecules that allosterically regulate protein activity by targeting protein–protein interactions is proposed. Expand
Structure–Activity Studies of Bis‐O‐Arylglycolamides: Inhibitors of the Integrated Stress Response
TLDR
The SAR studies described herein support the proposed pharmacology of ISRIB analogues as binding across a symmetrical protein–protein interface formed between protein subunits of the dimeric eIF2B heteropentamer. Expand
Predicting and improving the membrane permeability of peptidic small molecules.
TLDR
This work finds that the intentional introduction of hydrogen bond acceptor-donor pairs in peptidic small molecules can improve membrane permeability while retaining or improving other favorable drug-like properties. Expand
Microtubule Targeting Agents
TLDR
In this chapter agents that interact directly with microtubule dynamics are divided into two groups: (1) agents that promote the depolymerization of microtubules or otherwise destabilizemicrotubules; and (2) agent that promote polymerization ofmicrotubule or otherwise stabilizeMicrotubules. Expand
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