Biology subjects

Martins, L. C.

Publications and source records attributed to Martins, L. C..

3 recordsLinked to original sources

bioRxiv2026

Discovery of Semicarbazone and Thiosemicarbazone Analogs as Competitive SARS-CoV-2 Virus Main Protease (Mpro) Inhibitors

Despite the development of vaccines and antivirals, coronavirus disease 2019 (COVID-19) continues to affect populations worldwide. Given the high mutation rate of the SARS-CoV-2 virus and reports of drug resistance, there is a continued need for new therapeutic options. SARS-CoV-2 main protease (Mpro) is essential for viral replication and is a conserved target among coronaviruses. Most known Mpro inhibitors target the active site, although allosteric sites have already been identified. In this study, we conducted a virtual screening of 2,060 compounds targeting an allosteric site of SARS-CoV-2 Mpro. From this screen, 41 computational hits and analogs were selected and evaluated using biochemical assays against SARS-CoV-2 Mpro. Among them, compound 25, a semicarbazone, demonstrated a half-maximal inhibitory concentration (IC50) of 99 M. Additionally, two thiosemicarbazone analogs (compounds 50 and 51) inhibited SARS-CoV-2 Mpro with IC50 values of 61 M and 70 M. Biochemical assays suggest that these compounds act as noncovalent competitive inhibitors of SARS-CoV-2 Mpro. Molecular dynamics simulations revealed that compound 25 is unstable at the allosteric site of SARS-CoV-2 Mpro but forms stable and favorable interactions at the active site, supporting its potential as a competitive inhibitor, a finding subsequently confirmed by biochemical assays. Our structure-based computational and biochemical approach identified semicarbazone and thiosemicarbazone scaffolds as promising candidates for the development of reversible SARS-CoV-2 Mpro inhibitors.

biochemistry↗

bioRxiv2026

The Role of Conformational Changes in TcmN Aromatase/Cyclase in Polyketide Biosynthesis

Polyketide biosynthesis relies on the conformational adaptability of type II polyketide synthases and accessory enzymes, which direct chain folding and regiospecific cyclization. The aromatase/cyclase TcmN from Streptomyces glaucescensis catalyzes the first two ring closures of tetracenomycin C. Still, the molecular basis by which conformational dynamics regulate substrate binding and product release remains unresolved. Understanding how conformational transitions control ligand recognition and prevent aggregation is crucial for deciphering the molecular bases of polyketide biosynthesis and for guiding engineering strategies to synthesize novel natural products. Here, we investigated how ligand interactions modulate the conformational equilibrium of TcmN and the mechanistic consequences for catalysis. Using NMR spectroscopy (STD, CSP, relaxation dispersion), calorimetry, molecular docking, and microsecond-scale molecular dynamics simulations, we mapped the conformational ensembles of apo TcmN and its complexes with naringenin (a substrate/product analogue) and intermediate 12 (INT12). Apo TcmN samples both open and closed conformations. Naringenin preferentially stabilizes the closed state, a conformation thought to protect hydrophobic residues from solvent exposure. In contrast, INT12 shifts the equilibrium toward the open state, characterized by an expanded cavity that permits substrate entry, product release, and accommodation of extended intermediates. Hydrogen-bond analysis highlighted conserved catalytic residues (R82, E34, Q110, T133) as key anchors for productive poses. These results establish that TcmN functions through a ligand-gated breathing mechanism, in which successive intermediates selectively tune the cavity volume and shape, balancing catalytic efficiency with protection against aggregation. Conformational adaptability emerges as a central determinant of aromatase/cyclase function, providing molecular insights relevant for polyketide biosynthetic engineering. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/708631v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@5646aorg.highwire.dtl.DTLVardef@39016org.highwire.dtl.DTLVardef@1e8c285org.highwire.dtl.DTLVardef@3aba20_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Occurrence Of Avian Reovirus And Picobirnavirus In Wild Birds In An Environmental Protection Area In The Amazon Biome, Para, Brazil

Wild birds have great prominence on transmission of diseases to humans, mainly due to their ease of access to human population, raising concerns about the potential impact of that proximity in context of the One Health. Studies referring to circulation of avian reovirus (ARV) and picobirnavirus (PBV) in wild birds are limited, in addition to reinforcing the development of researches that describe the prevalence, characterize the variants and evaluate the potential impact of these infections on the wild ecosystem and public health. The present study reports the occurrence of ARV and PBV in wild birds collected from an environmental protection area in the Amazon biome. RT-PCR analysis showed ARV infection prevalence in 0.6% (1/155) and PBV infection in 1.29% (2/155) on the samples. ARV strain isolated in this study demonstrated more phylogenetically related to other ARVs previously circulating in poultry in the same region. The two PBV strains obtained belong to genogroup I, and showed phylogenetically related to other PBV isolated from different animal species in different geographic regions. This study is a pioneer in the detection of ARV in wild birds in Brazil and presents a report of the first occurrence of PBV in wild birds of Guira guira specie. Additional studies in wild birds are required to increase the epidemiology, origin, evolution and emergence of new viruses that may provoke problems in the context of One Health.

microbiology↗