6 research outputs found
Synthesis of taxane cyclization precursors
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1997.Includes bibliographical references.by Edcon Chang.Ph.D
Systems-Based Design of Bi-Ligand Inhibitors of Oxidoreductases: Filling the Chemical Proteomic Toolbox
Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases
Host Kinase CSNK2 is a Target for Inhibition of Pathogenic SARS-like β-Coronaviruses
Inhibition of the protein kinase CSNK2 with any of 30 specific and selective inhibitors representing different chemotypes, blocked replication of pathogenic human, bat, and murine β-coronaviruses. The potency of in-cell CSNK2A target engagement across the set of inhibitors correlated with antiviral activity and genetic knockdown confirmed the essential role of the CSNK2 holoenzyme in β-coronavirus replication. Spike protein endocytosis was blocked by CSNK2A inhibition, indicating that antiviral activity was due in part to a suppression of viral entry. CSNK2A inhibition may be a viable target for the development of anti-SARS-like β-coronavirus drugs
Optimization of 3‑Cyano-7-cyclopropylamino-pyrazolo[1,5‑<i>a</i>]pyrimidines toward the Development of an In Vivo Chemical Probe for CSNK2A
3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines,
including the chemical probe SGC-CK2-1, are potent and selective inhibitors
of CSNK2A in cells but have limited utility in animal models due to
their poor pharmacokinetic properties. While developing analogues
with reduced intrinsic clearance and the potential for sustained exposure
in mice, we discovered that phase II conjugation by GST enzymes was
a major metabolic transformation in hepatocytes. A protocol for codosing
with ethacrynic acid, a covalent reversible GST inhibitor, was developed
to improve the exposure of analogue 2h in mice. A double
codosing protocol, using a combination of ethacrynic acid and irreversible
P450 inhibitor 1-aminobenzotriazole, increased the blood level of 2h by 40-fold at a 5 h time point
Discovery of a Druggable, Cryptic Pocket in SARS-CoV‑2 nsp16 Using Allosteric Inhibitors
A collaborative, open-science team undertook discovery
of novel
small molecule inhibitors of the SARS-CoV-2 nsp16-nsp10 2′-O-methyltransferase using a high throughput screening approach
with the potential to reveal new inhibition strategies. This screen
yielded compound 5a, a ligand possessing an electron-deficient
double bond, as an inhibitor of SARS-CoV-2 nsp16 activity. Surprisingly,
X-ray crystal structures revealed that 5a covalently
binds within a previously unrecognized cryptic pocket near the S-adenosylmethionine binding cleft in a manner that prevents
occupation by S-adenosylmethionine. Using a multidisciplinary
approach, we examined the mechanism of binding of compound 5a to the nsp16 cryptic pocket and developed 5a derivatives
that inhibited nsp16 activity and murine hepatitis virus replication
in rat lung epithelial cells but proved cytotoxic to cell lines canonically
used to examine SARS-CoV-2 infection. Our study reveals the druggability
of this newly discovered SARS-CoV-2 nsp16 cryptic pocket, provides
novel tool compounds to explore the site, and suggests a new approach
for discovery of nsp16 inhibition-based pan-coronavirus therapeutics
through structure-guided drug design