Triplet repeats in human genome: distribution and their association with genes and other genomic regions

Motivation: Simple sequence repeats (SSRs) or microsatellite repeats are found abundantly in many prokaryotic and eukaryotic genomes. Among SSRs, triplet repeats are of special significance because some of them have been linked to various genetic disorders. The objective of the study is to analyze the triplet repeats of complete human genome and to identify the genes that contain the triplet repeats in their coding region. The analysis will help us to identify the candidate genes that have potential for repeat expansion. Results: We have analyzed triplet repeats in the complete human genome from the publicly available sequences. Our analysis revealed that AGC and CCG repeat were predominantly present in the coding regions of the genome while UTRs and the upstream sequences contained CCG repeats in relative abundance. Analysis of density of triplet repeats (bp/Mb) revealed that AAT and AAC were the abundant repeats whereas ACT and ACG were the rare repeats found in human genome. We could identify about 2135 known or predicted genes that were associated with at least one of the triplet repeat types. A large proportion of putative transcripts that were identified by gene finding programs were found to be associated with triplet repeats. These transcripts will be the candidate genes for analysis of triplet repeat expansion and a possible association with disease phenotypes. Identification of 171 genes which contain a minimum of ten repeat units will be of particular interest in future in correlating their association with any disease phenotype due to the expansion potential of repeats present in them. The list of genes and other details of analysis are given in the online supplementary data (http://www.ingenovis.com/tripletrepeats)

MRD: a microsatellite repeats database for prokaryotic and eukaryotic genomes

MRD is a database system to access the microsatellite repeats information of genomes such as archea, eubacteria, and other eukaryotic genomes whose sequence information is available in public domains. MRD stores information about simple tandemly repeated k-mer sequences where k= 1 to 6, i.e. monomer to hexamer. The web interface allows the users to search for the repeat of their interest and to know about the association of the repeat with genes and genomic regions in the specific organism. The data contains the abundance and distribution of microsatellites in the coding and non-coding regions of the genome. The exact location of repeats with respect to genomic regions of interest (such as UTR, exon, intron or intergenic regions) whichever is applicable to organism is highlighted. MRD is available on the World Wide Web at http://www.ccmb.res.in/mrd webcite and/or http://www.ingenovis.com/mrd webcite. The database is designed as an open-ended system to accommodate the microsatellite repeats information of other genomes whose complete sequences will be available in future through public domain

Structure-activity relationship and mechanism of action studies of manzamine analogues for the control of neuroinflammation and cerebral infections

Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinal isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g., Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3beta (GSK-3beta), which is a putative target of manzamines. On the basis of the results presented here, it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases

Discovery of Potent and Selective A_2A Antagonists with Efficacy in Animal Models of Parkinson’s Disease and Depression

Adenosine A_2A receptor (A_2AAdoR) antagonism is a nondopaminergic approach to Parkinson’s disease treatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4-morpholino-benzothiazole derivatives as A_2AAdoR antagonists. We herein described a novel series of [1,2,4]­triazolo­[5,1-<i>f</i>]­purin-2-one derivatives that displays functional antagonism of the A_2A receptor with a high degree of selectivity over A₁, A_2B, and A₃ receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound <b>33</b>. Compound <b>33</b> endowed with satisfactory <i>in vitro</i> and <i>in vivo</i> pharmacokinetics properties. Compound <b>33</b> demonstrated robust oral efficacies in two commonly used models of Parkinson’s disease (haloperidol-induced catalepsy and 6-OHDA lesioned rat models) and depression (TST and FST mice models)