Substituting Nε-thioacetyl-lysine for Nε-acetyl-lysine in Peptide Substrates as a General Approach to Inhibiting Human NAD+-dependent Protein Deacetylases

Inhibitors of human NAD+-dependent protein deacetylases possess great value for deciphering the biology of these enzymes and as potential therapeutics for metabolic and age-related diseases and cancer. In the current study, we have experimentally demonstrated that, the potent inhibition we obtained previously for one of these enzymes (i.e. sirtuin type 1 (SIRT1)) by simply replacing Nε-thioacetyl-lysine for Nε-acetyl-lysine in its peptide substrate, represented a general and efficient strategy to develop potent and selective inhibitors of human NAD+-dependent protein deacetylase enzymes. Indeed, by using this simple inhibition strategy, potent (low-micromolar) and selective (≤40-fold) SIRT2 and SIRT3 inhibitors, which were either comparable or superior to currently existing inhibitors, have also been quickly identified in the current study. These inhibitors could be used as chemical biological tools or as lead compounds for further focused structure-activity optimization

Isoxazole-Derived Amino Acids are Bromodomain-Binding Acetyl-Lysine Mimics: Incorporation into Histone H4 Peptides and Histone H3.

A range of isoxazole-containing amino acids was synthesized that displaced acetyl-lysine-containing peptides from the BAZ2A, BRD4(1), and BRD9 bromodomains. Three of these amino acids were incorporated into a histone H4-mimicking peptide and their affinity for BRD4(1) was assessed. Affinities of the isoxazole-containing peptides are comparable to those of a hyperacetylated histone H4-mimicking cognate peptide, and demonstrated a dependence on the position at which the unnatural residue was incorporated. An isoxazole-based alkylating agent was developed to selectively alkylate cysteine residues in situ. Selective monoalkylation of a histone H4-mimicking peptide, containing a lysine to cysteine residue substitution (K12C), resulted in acetyl-lysine mimic incorporation, with high affinity for the BRD4 bromodomain. The same technology was used to alkylate a K18C mutant of histone H3.Pfizer Neusentis for studentship suppor

Perceived Discrimination, Internalized Homonegativity, and Mental Health Symptoms: Comparative Analysis of Russian and United States LGB Populations

The Russian LGB community is one of the most oppressed communities in the world and the oppression is reinforced on a federal level with laws that violate the human rights of LGB individuals in Russia. This study examined the level of perceived discrimination, internalized homonegativity, and the level of mental health symptoms, including the symptoms of depression and anxiety, in a sample of 100 LGB individuals residing in Russia in comparison to a sample of 78 LGB individuals residing in the United States. The results indicated that Russian residents did not have significantly higher symptoms of depression and anxiety, perceived discrimination, and internalized homonegativity. Correlation analysis indicated no positive correlation between internalized homonegativity and mental health symptoms in Russian LGB individuals in contrast to U.S. LGB individuals. As homophobia has been the social norm in Russia, many LGB individuals who display homophobic feelings avoid stress and mental health issues. It is likely that they are less “out” as compared to their U.S. counterparts. This study demonstrated that the results of LGB oppression have similar effects on mental health in both Russia and the US. However, the Russian LGB individuals understood oppression, discrimination, and the need for human rights activism differently than the U.S. LGB participants. The approaches to the treatment of anxiety and depression in the Russian and U.S. LGB communities might be similar, but clinicians must be sensitive to a Russian cultural difference in their perception of this topic