Identification of Aryl Polyamines Derivatives as Anti- Agents Targeting Iron Superoxide Dismutase.

Chagas disease (CD) is a tropical and potentially fatal infection caused by . Although CD was limited to Latin America as a silent disease, CD has become widespread as a result of globalization. Currently, 6-8 million people are infected worldwide, and no effective treatment is available.

Three-Finger Toxins from Brazilian Coral Snakes: From Molecular Framework to Insights in Biological Function.

Studies on 3FTxs around the world are showing the amazing diversity in these proteins both in structure and function. In Brazil, we have not realized the broad variety of their amino acid sequences and probable diversified structures and targets. In this context, this work aims to conduct an in silico systematic study on available 3FTxs found in Micrurus species from Brazil.

Aerolysin nanopores decode digital information stored in tailored macromolecular analytes.

Digital data storage is a growing need for our society and finding alternative solutions than those based on silicon or magnetic tapes is a challenge in the era of "big data." The recent development of polymers that can store information at the molecular level has opened up new opportunities for ultrahigh density data storage, long-term archival, anticounterfeiting systems, and molecular cryptography. However, synthetic informational polymers are so far only deciphered by tandem mass spectrometry.

In Vivo Biological Evaluation of a Synthetic Royleanone Derivative as a Promising Fast-Acting Trypanocidal Agent by Inducing Mitochondrial-Dependent Necrosis.

The life-long and life-threatening Chagas disease is one of the most neglected tropical diseases caused by the protozoan parasite . It is a major public health problem in Latin America, as six to seven million people are infected, being the principal cause of mortality in many endemic regions. Moreover, Chagas disease has become widespread due to migrant populations.

Repositioning of leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts for Chagas disease treatment: Trypanosoma cruzi cell death involving mitochondrial membrane depolarisation and Fe-SOD inhibition.

Trypanosomatidae is a family of unicellular parasites belonging to the phylum Euglenozoa, which are causative agents in high impact human diseases such as Leishmaniasis, Chagas disease and African sleeping sickness. The impact on human health and local economies, together with a lack of satisfactory chemotherapeutic treatments and effective vaccines, justifies stringent research efforts to search for new disease therapies. Here, we present in vitro trypanocidal activity data and mode of action data, repositioning leishmanicidal [1,2,3]Triazolo[1,5-a]pyridinium salts against Trypanosoma cruzi, the aetiological agent of Chagas disease.

Single-molecule sensing of peptides and nucleic acids by engineered aerolysin nanopores.

Nanopore sensing is a powerful single-molecule approach for the detection of biomolecules. Recent studies have demonstrated that aerolysin is a promising candidate to improve the accuracy of DNA sequencing and to develop novel single-molecule proteomic strategies. However, the structure-function relationship between the aerolysin nanopore and its molecular sensing properties remains insufficiently explored.

Rational modification of Mannich base-type derivatives as novel antichagasic compounds: Synthesis, in vitro and in vivo evaluation.

The current chemotherapy against Chagas disease is inadequate and insufficient. A series of ten Mannich base-type derivatives have been synthesized to evaluate their in vitro antichagasic activity. After a preliminary screening, compounds 7 and 9 were subjected to in vivo assays in a murine model.

A step towards development of promising trypanocidal agents: Synthesis, characterization and in vitro biological evaluation of ferrocenyl Mannich base-type derivatives.

Chagas disease is a neglected chronical parasitosis caused by the parasite Trypanosoma cruzi (T. cruzi). Nine ferrocenyl Mannich base derivatives were synthetized and characterized to explore their in vitro activity on three T.

Mapping the sensing spots of aerolysin for single oligonucleotides analysis.

Nanopore sensing is a powerful single-molecule method for DNA and protein sequencing. Recent studies have demonstrated that aerolysin exhibits a high sensitivity for single-molecule detection. However, the lack of the atomic resolution structure of aerolysin pore has hindered the understanding of its sensing capabilities.

Second Generation of Mannich Base-Type Derivatives with in Vivo Activity against Trypanosoma cruzi.

Chagas disease is a potentially life-threatening and neglected tropical disease caused by Trypanosoma cruzi. One of the most important challenges related to Chagas disease is the search for new, safe, effective, and affordable drugs since the current therapeutic arsenal is inadequate and insufficient. Here, we report a simple and cost-effective synthesis and the biological evaluation of the second generation of Mannich base-type derivatives.

Structural, physicochemical and dynamic features conserved within the aerolysin pore-forming toxin family.

Aerolysin is the founding member of a major class of β-pore-forming toxins (β-PFTs) found throughout all kingdoms of life. PFTs are cytotoxic proteins produced as soluble monomers, which oligomerize at the membrane of target host cells forming pores that may lead to osmotic lysis and cell death. Besides their role in microbial infection, they have become interesting for their potential as biotechnological sensors and delivery systems.

In Vitro and in Vivo Anti-Trypanosoma cruzi Activity of New Arylamine Mannich Base-Type Derivatives.

Chagas disease is a neglected tropical disease with 6-7 million people infected worldwide, and there is no effective treatment. Therefore, there is an urgent need to continue researching in order to discover novel therapeutic alternatives. We present a series of arylaminoketone derivatives as means of identifying new drugs to treat Chagas disease in the acute phase with greater activity, less toxicity, and a larger spectrum of action than that corresponding to the reference drug benznidazole.

Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore-formation process.

Owing to their pathogenical role and unique ability to exist both as soluble proteins and transmembrane complexes, pore-forming toxins (PFTs) have been a focus of microbiologists and structural biologists for decades. PFTs are generally secreted as water-soluble monomers and subsequently bind the membrane of target cells. Then, they assemble into circular oligomers, which undergo conformational changes that allow membrane insertion leading to pore formation and potentially cell death.

Novel sulfonylurea derivatives as H3 receptor antagonists. Preliminary SAR studies.

The combination of antagonism at histamine H(3) receptor and the stimulation of insulin secretion have been proposed as an approach to new dual therapeutic agents for the treatment of type 2 diabetes mellitus associated with obesity. We have designed and synthesized a new series of non-imidazole derivatives, based on a basic amine ring connected through an alkyl spacer of variable length to a phenoxysulfonylurea moiety. These compounds were initially evaluated for histamine H(3) receptor binding affinities, suggesting that a propoxy chain linker between the amine and the core ring could be essential for optimal binding affinity.

Building a MCHR1 homology model provides insight into the receptor-antagonist contacts that are important for the development of new anti-obesity agents.

Melanin-concentrating hormone (MCH) regulates feeding and energy homeostasis through interaction with its receptor, the melanin-concentrating receptor 1 (MCHR1), making it a target in the treatment of obesity. Molecular modeling and docking studies were performed in order to find a binding model for the docking of two new series of MCHR1 antagonists to the receptor. Results suggested interactions between the ligands and two glutamines (Gln5.

New amide derivatives as melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity.

Melanin-concentrating hormone (MCH) is a recently discovered central nervous system (CNS) target for treating obesity. Two novel series of amide derivatives were synthesized and evaluated biologically as MCH-R1 (melanin-concentrating hormone receptor 1) antagonists. The results showed that diphenyl substituents on the amide lead to better activity than biphenyl substituents.

Melanin-concentrating hormone receptor 1 antagonists: a new perspective for the pharmacologic treatment of obesity.

Obesity is a chronic disease characterized by the accumulation of excess adipose tissue associated with an increased risk of multiple morbidities and mortality. At the present time, only three drugs have been approved by the Food and Drug Administration (FDA) for the treatment of obesity. Agonists and antagonists of some of the substances implicated in the regulation of energy homeostasis represent opportunities for anti-obesity drug development.

Novel series of substituted biphenylmethyl urea derivatives as MCH-R1 antagonists for the treatment of obesity.

We have designed and synthesized two novel series of MCH-R1 antagonists based on a substituted biphenylmethyl urea core. SAR was explored, suggesting that optimal binding with the receptor was achieved when the biphenylmethyl group and the linker were substituted on the same nitrogen of the urea moiety. Compound 1-(3'-cyano-4-biphenylmethyl)-3-(2-hydroxy-1,1-dimethylethyl)-1-{2-[1-(4-methylbenzyl)-4-piperidinyl]ethyl}urea 2t showed the best antagonist binding activity to the MCH-R1 with a 43 nM K(i).