Publications by authors named "Yasser Almeida Hernandez"

Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity.

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Activation of the replicative Mcm2-7 helicase by loading GINS and Cdc45 is crucial for replication origin firing, and as such for faithful genetic inheritance. Our biochemical and structural studies demonstrate that the helicase activator GINS interacts with TopBP1 through two separate binding surfaces, the first involving a stretch of highly conserved amino acids in the TopBP1-GINI region, the second a surface on TopBP1-BRCT4. The two surfaces bind to opposite ends of the A domain of the GINS subunit Psf1.

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EPI-X4, a natural peptide CXCR4 antagonist, shows potential for treating inflammation and cancer, but its short plasma stability limits its clinical application. We aimed to improve the plasma stability of EPI-X4 analogues without compromising CXCR4 antagonism. Our findings revealed that only the peptide N-terminus is prone to degradation.

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Whooping cough is a severe childhood disease, caused by the bacterium , which releases pertussis toxin (PT) as a major virulence factor. Previously, we identified the human antimicrobial peptides α-defensin-1 and -5 as inhibitors of PT and demonstrated their capacity to inhibit the activity of the PT enzyme subunit PTS1. Here, the underlying mechanism of toxin inhibition was investigated in more detail, which is essential for developing the therapeutic potential of these peptides.

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Semen is an important vector for sexual HIV-1 transmission. Although CXCR4-tropic (X4) HIV-1 may be present in semen, almost exclusively CCR5-tropic (R5) HIV-1 causes systemic infection after sexual intercourse. To identify factors that may limit sexual X4-HIV-1 transmission, we generated a seminal fluid-derived compound library and screened it for antiviral agents.

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The peptide fragment of human serum albumin that was identified as an inhibitor of C-X-C motif chemokine receptor 4 (CXCR4), termed EPI-X4, was investigated as a scaffold for the development of CXCR4-targeting radio-theragnostics. Derivatives of its truncated version JM#21 (ILRWSRKLPCVS) were conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and tested in Jurkat and Ghost-CXCR4 cells. Ligand-, -, -, -, -, -, and - were selected for radiolabeling.

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Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion.

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Peptides are prime drug candidates due to their high specificity of action but are disadvantaged by low proteolytic stability. Here, we focus on the development of stabilized analogues of EPI-X4, an endogenous peptide antagonist of CXCR4. We synthesized macromolecular peptide conjugates and performed side-by-side comparison with their albumin-binding counterparts and considered monovalent conjugates, divalent telechelic conjugates, and Y-shaped peptide dimers.

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The GlpG rhomboid protease from is a well-characterized intramembrane protease that cleaves transmembrane substrates inside the lipid bilayer. Most studies have focused on the GlpG transmembrane domain containing the catalytic site, while the full-length protein, also containing a soluble cytoplasmic domain, a linker region, and a small positively charged C-terminal fragment, remains poorly understood. In this work, we used coarse-grained molecular dynamics (CGMD) simulations to investigate full-length GlpG embedded in a native-like model of the membrane.

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Article Synopsis
  • Human syncytial respiratory virus (HRSV) is a negative-strand RNA virus that primarily affects infants and has been reclassified into the Pneumoviridae family due to its unique features.
  • The virus has a transcriptional antiterminator named M, which plays a crucial role in RNA synthesis and is unusual among viruses, making its mechanism of action intriguing to researchers.
  • Recent studies provide a detailed crystal structure of the M protein, revealing important insights into its RNA-binding domain and stability, which could have implications for understanding transcription regulation and developing antiviral therapies.
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A crucial bottleneck in membrane protein structural biology is the difficulty in identifying a detergent that can maintain the stability and functionality of integral membrane proteins (IMPs). Detergents are poor membrane mimics, and their common use in membrane protein crystallography may be one reason for the challenges in obtaining high-resolution crystal structures of many IMP families. Lipid-like peptides (LLPs) have detergent-like properties and have been proposed as alternatives for the solubilization of G protein-coupled receptors and other membrane proteins.

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Energy coupling factor (ECF) transporters are responsible for the uptake of essential scarce nutrients in prokaryotes. This ATP-binding cassette transporter family comprises two subgroups that share a common architecture forming a tripartite membrane protein complex consisting of a translocation component and ATP hydrolyzing module and a substrate-capture (S) component. Here, we present the crystal structure of YkoE from Bacillus subtilis, the S component of the previously uncharacterized group I ECF transporter YkoEDC.

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