Combinatorial synthesis of a hyaluronan based polysaccharide library for enhanced CD44 binding.

Hyaluronan (HA) plays important roles in a wide range of biological events. The principal receptor of HA in the human body is the Cluster of Differentiation 44 (CD44). To enhance the binding between HA and CD44, a new approach was designed to take advantage of the four-component Ugi reaction.

Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.

Since the discovery of the caspase-2 (Casp2)-mediated ∆tau314 cleavage product and its associated impact on tauopathies such as Alzheimer's disease, the design of selective Casp2 inhibitors has become a focus in medicinal chemistry research. In the search for new lead structures with respect to Casp2 selectivity and drug-likeness, we have taken an approach by looking more closely at the specific sites of Casp2-mediated proteolysis. Using seven selected protein cleavage sequences, we synthesized a peptide series of 53 novel molecules and studied them using in vitro pharmacology, molecular modeling, and crystallography.

Structure-Based Design and Biological Evaluation of Novel Caspase-2 Inhibitors Based on the Peptide AcVDVAD-CHO and the Caspase-2-Mediated Tau Cleavage Sequence YKPVD314.

Alzheimer's disease (AD) was first described by Alois Alzheimer over 100 years ago, but there is still no overarching theory that can explain its cause in detail. There are also no effective therapies to treat either the cause or the associated symptoms of this devastating disease. A potential approach to better understand the pathogenesis of AD could be the development of selective caspase-2 (Casp2) probes, as we have shown that a Casp2-mediated cleavage product of tau (Δtau314) reversibly impairs cognitive and synaptic function in animal models of tauopathies.

Structural Characterization of the Human Cytosolic Malate Dehydrogenase I.

The first crystal structure of the human cytosolic malate dehydrogenase I (MDH1) is described. Structure determination at a high resolution (1.65 Å) followed production, isolation, and purification of human MDH1 using a bacterial expression system.