Advances in sickle cell disease treatment: From drug discovery until the patient monitoring

Sickle Cell Disease (SCD) is one of the most prevalent hematological diseases in the world. Despite the immense progress in molecular knowledge about SCD in last years few therapeutical sources are currently available. Nowadays the treatment is performed mainly with drugs such as hydroxyurea or other fetal hemoglobin inducers and chelating agents. This review summarizes current knowledge about the treatment and the advancements in drug design in order to discover more effective and safe drugs. Patient monitoring methods in SCD are also discussed. © 2011 Bentham Science Publishers Ltd.

The discovery of Foxl2 paralogs in chondrichthyan, coelacanth and tetrapod genomes reveals an ancient duplication in vertebrates

The Foxl2 (forkhead box L2) gene is an important member of the forkhead domain family, primarily responsible for the development of ovaries during female sex differentiation. The evolutionary studies conducted previously considered the presence of paralog Foxl2 copies only in teleosts. However, to search for possible paralog copies in other groups of vertebrates and ensure that all predicted copies were homolog to the Foxl2 gene, a broad evolutionary analysis was performed, based on the forkhead domain family. A total of 2464 sequences for the forkhead domain were recovered, and subsequently, 64 representative sequences for Foxl2 were used in the evolutionary analysis of this gene. The most important contribution of this study was the discovery of a new subgroup of Foxl2 copies (ortholog to Foxl2B) present in the chondrichthyan Callorhinchus milii, in the coelacanth Latimeria chalumnae, in the avian Taeniopygia guttata and in the marsupial Monodelphis domestica. This new scenario indicates a gene duplication event in an ancestor of gnathostomes. Furthermore, based on the analysis of the syntenic regions of both Foxl2 copies, the duplication event was not exclusive to Foxl2. Moreover, the duplicated copy distribution was shown to be complex across vertebrates, especially in tetrapods, and the results strongly support a loss of this copy in eutherian species. Finally, the scenario observed in this study suggests an update for Foxl2 gene nomenclature, extending the actual suggested teleost naming of Foxl2A and Foxl2B to all vertebrate sequences and contributing to the establishment of a new evolutionary context for the Foxl2 gene. © 2013 Macmillan Publishers Limited All rights reserved.

Biotechnology of polyketides: new breath of life for the novel antibiotic genetic pathways discovery through metagenomics

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Anti dermatophytic therapy: prospects for the discovery of new drugs from natural products

Millions of people and animals suffer from superficial infections caused by a group of highly specialized filamentous fungi, the dermatophytes, which only infect keratinized structures. With the appearance of AIDS, the incidence of dermatophytosis has increased. Current drug therapy used for these infections is often toxic, long-term, and expensive and has limited effectiveness; therefore, the discovery of new anti dermatophytic compounds is a necessity. Natural products have been the most productive source for new drug development. This paper provides a brief review of the current literature regarding the presence of dermatophytes in immunocompromised patients, drug resistance to conventional treatments and new anti dermatophytic treatments.

Glycosomal Targets for Anti-Trypanosomatid Drug Discovery

Glycosomes are peroxisome-related organelles found in all kinetoplastid protists, including the human pathogenic species of the family Trypanosomatidae: Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. Glycosomes are unique in containing the majority of the glycolytic/gluconeogenic enzymes, but they also possess enzymes of several other important catabolic and anabolic pathways. The different metabolic processes are connected by shared co-factors and some metabolic intermediates, and their relative importance differs between the parasites or their distinct life-cycle stages, dependent on the environmental conditions encountered. By genetic or chemical means, a variety of glycosomal enzymes participating in different processes have been validated as drug targets. For several of these enzymes, as well as others that are likely crucial for proliferation, viability or virulence of the parasites, inhibitors have been obtained by different approaches such as compound libraries screening or design and synthesis. The efficacy and selectivity of some initially obtained inhibitors of parasite enzymes were further optimized by structure-activity relationship analysis, using available protein crystal structures. Several of the inhibitors cause growth inhibition of the clinically relevant stages of one or more parasitic trypanosomatid species and in some cases exert therapeutic effects in infected animals. The integrity of glycosomes and proper compartmentalization of at least several matrix enzymes is also crucial for the viability of the parasites. Therefore, proteins involved in the assembly of the organelles and transmembrane passage of substrates and products of glycosomal metabolism offer also promise as drug targets. Natural products with trypanocidal activity by affecting glycosomal integrity have been reported.

Novel bioassay for the discovery of inhibitors of the 2-C-Methyl-D-erythritol 4-Phosphate (MEP) and terpenoid pathways leading to carotenoid biosynthesis

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Discovery of a new antiviral protein isolated Lonomia obliqua analysed by bioinformatics and real-time approaches

This study presents a new recombinant protein that acts as a powerful antiviral (rAVLO—recombinant Antiviral protein of Lonomia obliqua). It was able to reduce the replication by 106 fold for herpes virus and by 104 fold for rubella virus. RT-PCR of viral RNA rAVLO treated infected cells also showed similar rate of inhibition in replication. The analysis of this protein by bioinformatics suggests that this protein is globular, secreted with a signal peptide and has the ability to bind to MHC class I. It was found that there are several protein binding sites with various HLA and a prevalence of α-helices in the N-terminal region (overall classified as a α/β protein type). BLAST similarity sequence search for corresponding cDNA did not reveal a similar sequence in Genbank, suggesting that it is from a novel protein family. In this study we have observed that this recombinant protein and hemolymph has a potent antiviral action. This protein was produced in a baculovirus/Sf-9 system. Therefore, these analyses suggest that this novel polypeptide is a candidate as a broad spectrum antiviral.

Current advances in antitubercular drug discovery: potent prototypes and new targets

Tuberculosis (TB) is an infectious disease caused by bacterium of the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World Health Organization aims to substantially reduce the number of cases in the coming years; however, the increased number of multidrug-resistant (MDR) and extremely drug-resistant (XDR) forms of the bacterium and the lack of treatment for latent tuberculosis are challenges to be overcome. In this review, we have identified the most potent compounds described in the literature during recent years with MIC values < 7 µM, low toxicity and a high selective index. In addition, emerging targets in MTB are presented to provide new perspectives for the discovery of new antitubercular drugs. This review aims to summarize the current advances in and promote insights into antitubercular drug discovery.

Antitubercular drug discovery: the molecular modification as promise tool

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)