Computational Study of the Allosteric Effects of p5 on CDK5-p25 Hyperactivity as Alternative Inhibitory Mechanisms in Neurodegeneration.

The cyclin-dependent kinase (CDK5) forms a stable complex with its activator p25, leading to the hyperphosphorylation of tau proteins and to the formation of plaques and tangles that are considered to be one of the typical causes of Alzheimer's disease (AD). Hence, the pathological CDK5-p25 complex is a promising therapeutic target for AD. Small peptides, obtained from the truncation of CDK5 physiological activator p35, have shown promise in inhibiting the pathological complex effectively while also crossing the blood-brain barrier. One such small 24-residue peptide, p5, has shown selective inhibition toward the pathological complex in vivo. Our previous research focused on the characterization of a computationally predicted CDK5-p5 binding mode and of its pharmacophore, which was consistent with competitive inhibition. In continuation of our previous work, herein, we investigate four additional binding modes to explore other possible mechanisms of interaction between CDK5 and p5. The quantitative description of the pharmacophore is consistent with both competitive and allosteric p5-induced inhibition mechanisms of CDK5-p25 pathology. The gained insights can direct further in vivo/in vitro tests and help design small peptides, linear or cyclic, or peptidomimetic compounds as adjuvants of orthosteric inhibitors or as part of a cocktail of drugs with enhanced effectiveness and lower side effects.

Extended delivery of non-steroidal anti-inflammatory drugs through contact lenses loaded with Vitamin E and cationic surfactants.

The purpose of this study is to extend drug release from ACUVUE Oasys® and ACUVUE TruEye® silicone hydrogel contact lenses by incorporation of vitamin E in conjunction with a cationic surfactant. In ACUVUE Oasys® and ACUVUE TruEye®, the release of ketorolac tromethamine and flurbiprofen sodium is extended from hours to several days for 11% and 21% vitamin E, (weight of vitamin E / weight of dry lens) but with a considerable reduction in the amount of drug released. Cetalkonium chloride and stearylamine increased the drug loading capacity which was otherwise compromised by the addition of vitamin E in the contact lenses. In the case of diclofenac sodium, a sustained release over 150 h for both contact lenses can be achieved. It was found that the release-time-increase factor due to vitamin E has a linear dependence with the octanol-water partition coefficient of the drug in ACUVUE Oasys®. The results in this study show that contact lenses loaded with vitamin E in conjunction with cationic surfactants achieved sustained release of non-steroidal anti-inflammatory drugs (NSAIDs) within the therapeutic window.