A Structure-Based Discovery Platform for BACE2 and the Development of Selective BACE Inhibitors.

The ability to perform routine structure-guided drug design for selective BACE inhibitors has been limited because of the lack of robust platform for BACE2 expression, purification, and crystallization. To overcome this limitation, we developed a platform that produces 2-3 mg of pure BACE2 protein per liter of culture, and we used this protein to design macrocyclic compounds that potently and selectively inhibit BACE1 over BACE2. Compound was found to potently inhibit BACE 1 ( = 5 nM) with a selectivity of 214-fold over BACE2.

Development of an Efficient Enzyme Production and Structure-Based Discovery Platform for BACE1 Inhibitors.

BACE1 (Beta-site Amyloid Precursor Protein (APP) Cleaving Enzyme 1) is a promising therapeutic target for Alzheimer's Disease (AD). However, efficient expression, purification, and crystallization systems are not well described or detailed in the literature nor are approaches for treatment of enzyme kinetic data for potent inhibitors well described. We therefore developed a platform for expression and purification of BACE1, including protein refolding from inclusion bodies, in addition to optimizing a reproducible crystallization procedure of BACE1 bound with inhibitors.

Mechanism of action of 4-substituted phenols to induce vitiligo and antimelanoma immunity.

Monobenzone is a 4-substituted phenol that can induce vitiligo and antimelanoma immunity. We investigated the influence of the chemical structure on the biological activity of a series of structurally related 4-substituted phenols. All phenols inhibited cellular melanin synthesis, and eight of ten phenols inhibited tyrosinase activity, using the MBTH assay.

Oxidation events and skin aging.

The rate of skin aging, or that of tissue in general, is determined by a variable predominance of tissue degeneration over tissue regeneration. This review discusses the role of oxidative events of tissue degeneration and aging in general, and for the skin in particular. The mechanisms involved in intrinsic and extrinsic (photo-) aging are described.