Label-free affinity screening, design and synthesis of inhibitors targeting the <i>Mycobacterium tuberculosis</i> L-alanine dehydrogenase

The ability of Mycobacterium tuberculosis (Mtb) to persist in its host may enable an evolutionary advantage for drug resistant variants to emerge. A potential strategy to prevent persistence and gain drug efficacy is to directly target the activity of enzymes that are crucial for persistence. We present a method for expedited discovery and structure-based design of lead compounds by targeting the hypoxia-associated enzyme L-alanine dehydrogenase (AlaDH). Biochemical and structural analyses of AlaDH confirmed binding of nucleoside derivatives and showed a site adjacent to the nucleoside binding pocket that can confer specificity to putative inhibitors. Using a combination of dye-ligand affinity chromatography, enzyme kinetics and protein crystallographic studies, we show the development and validation of drug prototypes. Crystal structures of AlaDH-inhibitor complexes with variations at the N6 position of the adenyl-moiety of the inhibitor provide insight into the molecular basis for the specificity of these compounds. We describe a drug-designing pipeline that aims to block Mtb to proliferate upon re-oxygenation by specifically blocking NAD accessibility to AlaDH. The collective approach to drug discovery was further evaluated through in silico analyses providing additional insight into an efficient drug development strategy that can be further assessed with the incorporation of in vivo studies

Progress in gene therapy for neurological disorders

Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy

New-Onset Diabetes Mellitus Among Parkinsonian Patients Treated with Long-term Quetiapine

Atypical antipsychotics (AA) are commonly used to manage drug-induced psychosis (DIP) in parkinsonian patients. In the treatment of schizophrenia, AA’s have been associated with increasing reports of new-onset diabetes mellitus (DM). This study examined the risk of developing new-onset DM among parkinsonian patients on long-term, low dose quetiapine. Fifty-three parkinsonian subjects (mean age: 71.3 years) taking an average quetiapine dose of 70.5 mg/day (range: 12.5–350 mg/day) for a mean duration of 21.3 months (range 3–61 months) were reviewed. Eight out of 53 subjects carried a diagnosis of DM prior to quetiapine treatment. Four out of 45 patients (8.9%) met criteria for new diagnosis of DM, giving a total prevalence rate of 22.6% (12 out of 53). This prevalence rate of 22.6% was slightly higher than that reported in the aged-matched general population (year 2003 DM prevalence = 17.3% for 65–74 years) but methodological differences could explain the difference. Larger epidemiologic studies will be needed to confirm these results as they could potentially impact a significant number of patients