David Alan Campbell

Functional profiling of the proteome with affinity labels

The analysis of proteomic samples with affinity labels has been firmly established as a tool for the post-genomic researcher. Recent examples highlight the advantages of profiling functionally active members of specific protein families to identify therapeutically relevant protein targets that have escaped normal physiological regulation leading to increased or decreased activity. This dysregulation may result from any number of biological changes that modulate a proteins activity; for example, post-translational modifications of the protein or an imbalance between the protein and its endogenous inhibitor(s). By providing a direct measure of a proteins functional activity, affinity probe analysis identifies these changes and allows investigators to focus their research efforts upon those proteins that are most likely to be responsible for the biological changes under evaluation.

Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors.

A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.

Malonyl α-mercaptoketones and α-mercaptoalcohols, a new class of matrix metalloproteinase inhibitors

Abstract A novel series of matrix metalloproteinase (MMP) inhibitors is described. Incorporation of a terminal α-mercaptoketone or α-mercaptoalcohol in the zinc binding domain of a series of inhibitors led to compounds exhibiting low nanomolar activity against collagenase-1 (MMP-1), stromelysin (MMP-3), and gelatinase-B (MMP-9).

Bicyclic cyanothiazolidines as novel dipeptidyl peptidase 4 inhibitors.

The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution.

Preparation of N-alkylated 5-oxo-3-carboxamyl-1,4-thiazinanes on solid support

A general method was developed to generate six-membered cyclic thiazinanes on solid support. Three diversity sites were introduced into this scaffold using primary amines, aldehydes, and 2-bromoalkanoic acids. The methodology to prepare individual cyclic thiazinanes as well as combinatorial libraries of these compounds is described.