Biology subjects

Melo-Filho, C.

Publications and source records attributed to Melo-Filho, C..

4 recordsLinked to original sources

bioRxiv2026

AI-Driven Discovery and BSL-4 Validation of Cross-Filovirus Ebola-Marburg Inhibitors and their Synergistic Combinations

Filovirus outbreaks caused by Ebola virus (EBOV) and Marburg virus (MARV), pose severe global health threats characterized by high rates of fatal hemorrhagic fever. While species-specific vaccines and therapeutic monoclonal antibodies are approved for Zaire ebolavirus, broadly-active therapeutics remain unavailable, leaving populations vulnerable to MARV and other pathogenic Ebola species, such as Bundibugyo (BDBV) and Sudan (SUDV) ebolaviruses. Here we report a computationally guided, infectious virus validated screening platform for the rapid discovery of broad-spectrum filovirus antivirals. By leveraging quantitative structure-activity relationship (QSAR) models, we screened 142,382 compounds in silico to prioritize 125 high-potential candidates. Subsequent dose-response and viability profiling identified 23 compounds exhibiting potent, low-micromolar pan-filovirus activity and favorable cytotoxicity profiles. Molecular docking indicates these compounds target conserved structural and functional domains--primarily the VP35 and L proteins--which may disrupt essential viral replication and immune antagonism. Furthermore, systematic combinatorial screening revealed three highly synergistic compound pairs, notably NCGC00113249-01 and NCGC00118008-01, demonstrating robust cross-species efficacy. By targeting conserved vulnerabilities across the filovirus family, this integrated in silico and in vitro pipeline provides a scalable framework to rapidly nominate and optimize synergistic therapeutic regimens against both endemic and emerging viral threats including BDBV. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/737586v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@531939org.highwire.dtl.DTLVardef@19d1454org.highwire.dtl.DTLVardef@1a1c9e3org.highwire.dtl.DTLVardef@cd861b_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Conserved Filovirus Proteins as Targets of Broad-Spectrum Antivirals

Filoviruses are enveloped, non-segmented, negative-strand RNA viruses belonging to the Filoviridae family, which includes five genera: Ebolavirus, Marburgvirus, Cuevavirus, Striavirus, and Thamnovirus. Members of this family cause severe and, often, fatal hemorrhagic fevers in humans and non-human primates, with high mortality rates. To date, only two filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), are known to infect humans and are listed as priority pathogens by the World Health Organization due to their potential for re-emergence and the current lack of effective vaccines and antiviral treatments. In this study, we identify and characterize conserved binding sites within key filoviral proteins to support the development of broad-spectrum, direct-acting antiviral agents. We validated the significance of these conserved regions for drug discovery using existing experimental data. Our analysis revealed notably high sequence similarity among proteins from filoviruses capable of infecting humans (EBOV, TAFV, BDBV, SUDV, MARV, and RAVV) compared to those from non-zoonotic species, with the highest conservation observed in the L and VP40 proteins--both critical for viral genome transcription and replication. Furthermore, we compiled and analyzed available experimental data on known antiviral compounds targeting these proteins, identifying several agents with cross-filovirus activity, including Galidesivir, Remdesivir, and Favipiravir. The integrated approach described here--combining sequence and structural conservation analysis with chemical structure and antiviral activity data--demonstrates a strategy that could be extended to the development of broad-spectrum therapeutics across multiple viral families. HIGHLIGHTSO_LIConserved filovirus sites targeted for broad-spectrum antivirals. C_LIO_LIStructural modeling identifies key antiviral binding sites. C_LIO_LIViral internal proteins are crucial targets for inhibition. C_LIO_LIRemdesivir validates conserved polymerase as a druggable target. C_LIO_LIStudy highlights need for pan-filovirus drug screening C_LI TOC GRAPHIC O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/678902v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@4fd25eorg.highwire.dtl.DTLVardef@7c4076org.highwire.dtl.DTLVardef@16c0961org.highwire.dtl.DTLVardef@1dbd8a0_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

Small Molecule Antiviral Compound Collection (SMACC): a database to support the discovery of broad-spectrum antiviral drug molecules.

Diseases caused by new viruses costs thousands if not millions of human lives and trillions of dollars in damage to the global economy. Despite the rapid development of vaccines for SARS-CoV-2, the lack of small molecule antiviral drugs that work against multiple viral families (broad-spectrum antivirals; BSAs) has left the entire worlds human population vulnerable to the infection between the beginning of the outbreak and the widespread availability of vaccines. Developing BSAs is an attractive, yet challenging, approach that could prevent the next, inevitable, viral outbreak from becoming a global catastrophe. To explore whether historical medicinal chemistry efforts suggest the possibility of discovering novel BSAs, we (i) identified, collected, curated, and integrated all chemical bioactivity data available in ChEMBL for molecules tested in respective assays for 13 emerging viruses that, based on published literature, hold the greatest potential threat to global human health; (ii) identified and solved the challenges related to data annotation accuracy including assay description ambiguity, missing cell or target information, and incorrect BioAssay Ontology (BAO) annotations; (iii) developed a highly curated and thoroughly annotated database of compounds tested in both phenotypic (21,392 entries) and target-based (11,123 entries) assays for these viruses; and (iv) identified a subset of compounds showing BSA activity. For the latter task, we eliminated inconclusive and annotated duplicative entries by checking the concordance between multiple assay results and identified eight compounds active against 3-4 viruses from the phenotypic data, 16 compounds active against two viruses from the target-based data, and 35 compounds active in at least one phenotypic and one target-based assay. The pilot version of our SMACC (Small Molecule Antiviral Compound Collection) database contains over 32,500 entries for 13 viruses. Our analysis indicates that previous research yielded very small number of BSA compounds. We posit that focused and coordinated efforts strategically targeting the discovery of such agents must be established and maintained going forward. The SMACC database publicly available at https://smacc.mml.unc.edu may serve as a reference for virologists and medicinal chemists working on the development of novel BSA agents in preparation for future viral outbreaks.

bioinformatics↗

bioRxiv2022

Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents

The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can interrupt SARS-CoV-2 replication without damaging ACE2s natural enzymatic function. Initial compounds were screened for binding to ACE2 but little interruption of ACE2 enzymatic activity. This set of compounds was extended by application of quantitative structure-activity analysis, which resulted in 512 virtual hits for further confirmatory screening. A subsequent SARS-CoV-2 replication assay revealed that five of these compounds inhibit SARS-CoV-2 replication in human cells. Further effort is required to completely determine the antiviral mechanism of these compounds, but they serve as a strong starting point for both development of acute treatments for COVID-19 and research into the mechanism of infection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/484484v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@173d7c9org.highwire.dtl.DTLVardef@5c0021org.highwire.dtl.DTLVardef@c9caaorg.highwire.dtl.DTLVardef@18d23_HPS_FORMAT_FIGEXP M_FIG TOC Graphic: Overall study design. C_FIG

bioinformatics↗