An update on the emerging approaches for histone deacetylase (HDAC) inhibitor drug discovery and future perspectives.

INTRODUCTION: HDACs catalyze the removal of acetyl groups from the ε-N-acetylated lysine residues of various protein substrates including both histone and nonhistone proteins. Different HDACs have distinct biological functions and are recruited to specific regions of the genome. HDAC inhibitors have attracted much attention in recent decades; indeed, there have been more than thirty HDAC inhibitors investigated in clinic trials with five approvals being achieved. AREAS COVERED: This review covers the emerging approaches for HDAC inhibitor drug discovery from the past five years and includes discussion of structure-based rational design, isoform selectivity, and dual mechanism/multi-targeting. Chemical structures in addition to the in vitro and in vivo inhibiting activity of these compounds have also been discussed. EXPERT OPINION: The exact role and biological functions of HDACs is still under investigation with a variety of HDAC inhibitors having been designed and evaluated. HDAC inhibitors have shown promise in treating cancer, AD, metabolic disease, viral infection, and multiple sclerosis, but there is still a lot of room for clinical improvement. In the future, more efforts should be put into (i) HDAC isoform identification (ii) the optimization of selectivity, activity, and pharmacokinetics; and (iii) unconventional approaches for discovering different effective scaffolds and pharmacophores.

The Activity of Small Urea-γ-AApeptides Toward Gram-Positive Bacteria.

Host Defense Peptides (HDPs) have gained considerable interest due to the omnipresent threat of bacterial infection as a serious public health concern. However, development of HDPs is impeded by several drawbacks, such as poor selectivity, susceptibility to proteolytic degradation, low-to-moderate activity and requiring complex syntheses. Herein we report a class of lipo-linear α/urea-γ-AApeptides with a hybrid backbone and low molecular weight. The heterogeneous backbone not only enhances chemodiversity, but also shows effective antimicrobial activity against Gram-positive bacteria and is capable of disrupting bacterial membranes and killing bacteria rapidly. Given their low molecular weight and ease of access via facile synthesis, they could be practical antibiotic agents.

Novel bis-cyclic guanidines as potent membrane-active antibacterial agents with therapeutic potential.

We designed a class of small dimeric cyclic guanidine derivatives which display potent antibacterial activity against both multidrug-resistant Gram-negative and Gram-positive bacteria. They could compromise bacterial membranes without developing resistance, inhibit biofilms formed by E. coli, and exhibit excellent in vivo activity in the MRSA-infected thigh burden mouse model.

The effects of nicotine on bone calcium and phosphorus content and alkaline phosphatase activity in different part of rat / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To analyze the effects of nicotine on the bone calcium and phosphorus content and alkaline phosphatase (ALP) activity in rat alveolar bone and mandible.</p><p><b>METHODS</b>Twenty health male Wistar rats of five weeks of age were randomly assigned to two groups and received daily intraperitoneal injections for three months as follows: Saline solution for control group, nicotine 0.73 mg.kg-l.d-1 for experimental group. The bone calcium phosphorus content were detected by concentrated acid digestion method and the ALP activity was examined by improved Reddi method.</p><p><b>RESULTS</b>Compared to the control group, bone calcium and phosphorus content was lower in the experimental group (P<0.05), ALP activity had no statistical significance(P>0.05). Bone calcium phosphorus and ALP activity in different parts had no statistical significance (P>0.05).</p><p><b>CONCLUSION</b>The nicotine reduces calcium phosphorus deposition of jaw bone, but has no obvious influence to ALP activity.</p>