Biology subjects

Machado de Avila, R. A.

Publications and source records attributed to Machado de Avila, R. A..

4 recordsLinked to original sources

bioRxiv2024

Treatment options for Chagas Disease: a systematic review and meta-analysis applied to the preclinical studies using animal models

Chagas disease (CD) is a neglected tropical disease endemic to Latin America and has emerged as a global health concern due to the migration of infected individuals. With its epidemiological complexity, difficulty in obtaining appropriate diagnoses, and poor treatment, the search for novel therapeutic options remains. In this context, we conducted a systematic review and meta-analysis of preclinical studies employing animal models to verify the progress in CD treatment. We searched the PubMed database for CD treatment studies published between 1990 and 2023, adhering to the PRISMA guidelines. Twelve papers met the inclusion criteria. The findings indicate that the fifteen treatment alternatives examined, mainly between 2010 and 2014, demonstrated efficacy in experimental CD models, evidenced by significant parasitemia reduction. Bis-triazole DO870 and VNI were effective in the acute and chronic phases, respectively. However, of these emerging therapies, only posaconazole and fexinidazole have progressed to clinical trials, yielding unsatisfactory outcomes as CD monotherapies. This meta-analysis highlights the existence of promising new drug candidates for CD treatment, but most remain in the preclinical stages. Those that reached clinical trials did not demonstrate optimal results, underscoring the ongoing challenges in CD therapy. Collaborative efforts among the academic community, pharmaceutical industries, funding agencies, and government agencies are urgently needed to accelerate the development of more effective medications against CD.

pathology↗

bioRxiv2024

Targeting Leishmania infantum Mannosyl-oligosaccharide glucosidase with natural products: pH-dependent inhibition explored through computer-aided drug design.

Visceral Leishmaniasis (VL) is a serious public health issue, documented in more than ninety countries, where an estimated 500,000 new cases emerge each year. Regardless of novel methodologies, advancements, and experimental interventions, therapeutic limitations, and drug resistance are still challenging. For this reason, based on previous research, we screened natural products (NP) from Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBEDB), Mexican Compound Database of Natural Products (BIOFACQUIM), and Peruvian Natural Products Database (PeruNPDB) databases, in addition to structural analogs of Miglitol and Acarbose, which have been suggested as treatments for VL and have shown encouraging action against parasites N-glycan biosynthesis. Using computer-aided drug design (CADD) approaches, the inhibitory effect of these NP candidates was evaluated by inhibiting the Mannosyl-oligosaccharide Glucosidase Protein (MOGS) from Leishmania infantum, an enzyme essential for the protein glycosylation process, at various pH to mimic the parasites changing environment. Also, computational analysis was used to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profile, while molecular dynamic simulations were used to gather information on the interactions between these ligands and the protein target. Our findings indicated that Ocotillone and Subsessiline have potential antileishmanial effects at pH 5 and 7, respectively, due to their high binding affinity to MOGS and interactions in the active center. Furthermore, these compounds were non-toxic and had the potential to be administered orally. This research indicates the promising anti-leishmanial activity of Ocotillone and Subsessiline, suggesting further validation through in vitro and in vivo experiments.

bioinformatics↗

bioRxiv2023

Targeting with structural analogs of natural products the purine salvage pathway in Leishmania (Leishmania) infantum by computer-aided drug design approaches

Visceral Leishmaniasis (VL) has a high death rate with 500,000 new cases and 50,000 deaths occurring annually. Despite the development of novel strategies and technologies, there is no adequate treatment for the disease. Therefore, the purpose of this study is to find structural analogs of natural products as potential novel drugs to treat VL. To choose structural analogs from natural products that have demonstrated anti-leishmanial and anti-adenine phosphoribosyltransferase (APRT) properties, and that might bind with several targets from the purine salvage pathway, we used computer-aided drug design (CADD) techniques. Computational techniques were used to study the purine salvage pathway from Leishmania infantum, and molecular dynamic simulations were used to gather information on the interactions between ligands and proteins. An analog of the alkaloid Skimmianine, N,N-diethyl-4-methoxy-1-benzofuran-6-carboxamide, demonstrated a good binding affinity to two L. infantum targets, no expected toxicity, and potential for oral route administration. This study indicates that the compounds may have anti-leishmanial activity, which granted in vitro and in vivo experiments to settle this finding in the future.

bioinformatics↗

bioRxiv2018

PEPOP: new approaches to mimic non-continous epitopes

Bioinformatics methods are helpful to identify new molecules for diagnostic or therapeutic applications. For example, the use of peptides capable of mimicking binding sites has several benefits as replacing a protein difficult to produce, or toxic. Using peptides is less expensive. Peptides are easier to manipulate, and can be used as drugs. Continuous epitope predicted by bioinformatics tools are commonly used and these sequential epitopes are used as such in further experiments. Numerous discontinuous epitope predictors have been developed but only two bioinformatics tools proposed so far to predict peptide sequences: Superficial and PEPOP. PEPOP can generate series of peptide sequences that can replace continuous or discontinuous epitopes in their interaction with their cognate antibody. We have developed an improved version of PEPOP dedicated to answer to the experimentalists need for a tool able to handle proteins and to turn them into peptides. The PEPOP web site has been reorganized by peptide prediction category and is therefore better formulated to experimental designs. Since the first version of PEPOP, 32 new methods of peptide design were developed. In total, PEPOP proposes 35 methods in which 34 deal specifically with discontinuous epitopes, the most represented epitope type in nature.\n\nWe present the user-friendly, well-structured web-site of PEPOP and its validation through the use of predicted immunogenic or antigenic peptides mimicking discontinuous epitopes in different experimental ways. PEPOP proposes 35 methods of peptide design to guide experimentalists in using peptides potentially capable of replacing the cognate protein in its interaction with an Ab.

bioinformatics↗