Development of Novel Immunoprophylactic Agents against Multidrug-Resistant Gram-Negative Bacterial Infections.

The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases.

Identification of bacteria-selective threonyl-tRNA synthetase substrate inhibitors by structure-based design.

A series of potent and bacteria-selective threonyl-tRNA synthetase (ThrRS) inhibitors have been identified using structure-based drug design. These compounds occupied the substrate binding site of ThrRS and showed excellent binding affinities for all of the bacterial orthologues tested. Some of the compounds displayed greatly improved bacterial selectivity.

Benzothiophene containing Rho kinase inhibitors: Efficacy in an animal model of glaucoma.

We identified a new benzothiophene containing Rho kinase inhibitor scaffold in an ultra high-throughput enzymatic activity screen. SAR studies, driven by a novel label-free cellular impedance assay, were used to derive 39, which substantially reduced intraocular pressure in a monkey model of glaucoma-associated ocular hypertension.

Allosteric inhibitors of hepatitis C polymerase: discovery of potent and orally bioavailable carbon-linked dihydropyrones.

The discovery and optimization of a novel class of carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement of the sulfur linker atom with carbon reduced compound acidity and greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to the identification of compounds, exemplified by 23 and 24, with significantly improved antiviral activities in the cell-based replicon assay and favorable pharmacokinetic profiles.

Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors.

A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.