Biology subjects

Chavez Fumagalli, M. A.

Publications and source records attributed to Chavez Fumagalli, M. A..

5 recordsLinked to original sources

bioRxiv2026

From Proteome Mining to Structural Validation: Phosphopyruvate Hydratase as a Structurally Tractable Drug Target in Kinetoplastid Parasites

Chagas disease, caused by Trypanosoma cruzi, demands novel therapeutic strategies that overcome the toxicity and limited efficacy of current treatments. To address this need, herein we report an integrative, target-centric strategy that combines parasite proteome mining, structural modeling, and experimental validation. Functional enrichment and druggability analyses identified phosphopyruvate hydratase (PPH) as a promising candidate due to its essential metabolic role and limited similarity to human homologs. Notably, proteome mining revealed the presence and conservation of PPH across kinetoplastid parasites, including Leishmania donovani, supporting its evaluation beyond T. cruzi. For the selected PPH sequences, AlphaFold-derived three-dimensional models underwent extensive molecular dynamics refinement, yielding stable conformational ensembles suitable for structure-based studies. Using this validated model, virtual screening of the Latin American Natural Products Database - LANaPDB - identified aptosimon as a top-ranked compound candidate. Molecular dynamics simulations further showed ligand-dependent binding behavior, suggesting alternative binding modes distinct from the canonical substrate configuration. In vitro assays demonstrated consistent antiparasitic activity against intracellular T. cruzi amastigotes (IC = 3.52 {+/-} 0.023 {micro}g/mL) and Leishmania donovani promastigotes (IC = 13.06 {+/-} 0.018 {micro}g/mL), supporting the biological relevance of the aptosimon-related lignan chemotype, hinokinin, across two kinetoplastid parasite models. Together, these results support PPH as a structurally tractable and biologically relevant candidate target, while identifying an aptosimon-related lignan chemotype, represented experimentally by hinokinin, as a cross-species antiparasitic scaffold that warrants further biochemical target-validation studies.

bioinformatics↗

bioRxiv2026

Rational in silico discovery and serological validation of Trypanosoma cruzi-specific B-cell epitopes for high-precision Chagas disease diagnosis

Chagas disease is caused by the parasite Trypanosoma cruzi and remains a neglected tropical disease presenting a substantial global health burden. Crude antigen-based assays have historically been limited in specificity; however, even contemporary recombinant-antigen tests may exhibit residual cross-reactivity, depending on antigen composition and geographic context. To overcome this limitation, this study developed a novel diagnostic strategy that integrates computational and experimental approaches to identify specific linear B-cell epitopes within the T. cruzi proteome. The strategy was developed to exclude sequences homologous to H. sapiens and Leishmania spp. proteins, thereby minimizing potential cross-reactivity. Using a consensus approach across five prediction algorithms, B-cell epitopes were identified and subsequently clustered to reveal conserved, immunoreactive consensus sequences. The peptide sequences were characterized for optimal physicochemical properties and subsequently modeled to interact with a human antibody using protein-peptide docking and molecular dynamics simulations to assess complex stability. The most promising candidates were chemically synthesized and validated using ELISA against a cohort comprising Chagas disease patients (chronic indeterminate and cardiac forms), healthy donors, and a cross-reactive control group (visceral and tegumentary leishmaniasis and leprosy). From the initial set of 19,245 proteins, the multi-tiered bioinformatic analysis identified 4,431 unique, non-homologous sequences. Consensus prediction yielded 401 high-confidence epitopes, which were refined to 179 structurally stable candidates. Computational analyses identified five top-ranking epitopes capable of forming high-affinity, stable complexes with a human antibody. Experimental validation confirmed the high diagnostic accuracy of two epitopes, which demonstrated exceptional diagnostic performance: Epitope 4 and Epitope 5 achieved 100% sensitivity. Notably, Epitope 5 exhibited superior specificity, reaching 96.67% against healthy controls and 90.91% against the cross-reactive group. This study establishes a basis for the development of an improved immunoassay for Chagas disease and provides a reproducible framework for targeted epitope discovery. Consequently, this study validates a high-precision computational pipeline capable of discovering T. cruzi-specific antigens that effectively circumvent cross-reactivity with Leishmania spp., proposing Epitope 5 as a qualified candidate for reliable serological diagnosis in co-endemic regions.

bioinformatics↗

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↗

bioRxiv2022

In silico-based screening for natural products structural analogs as new drugs candidate against leishmaniasis

Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Hence, this study aims to in silico screen for natural products structural analogs as new drugs candidate against leishmaniasis. We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation, and Molecular Mechanics-Generalized Born Surface Area MM/GBSA estimation aiming to select structural analogs from natural products that have shown antileishmanial activity against arginase (ARG) enzyme and that could bind selectively against Leishmania ARG. The compounds 2H-1-Benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), Echioidinin, and Malvidin showed good results against ARG targets from three parasite species and negative results for potential toxicities. The Malvidin ligand generated interactions in the active center at pH 2.0 conditions and hydrogen bonds enhancing receptor-ligand coupling. This work identified Malvidin as a potential drug candidate to treat leishmaniasis.

bioinformatics↗