Biology subjects

Carbajo, D.

Publications and source records attributed to Carbajo, D..

3 recordsLinked to original sources

bioRxiv2026

cis-gamma-Amino-L-proline peptides as chemical probes of amyloidogenic processing in neurons and APP/PS1 mice

Alzheimers disease (AD) is characterized by the accumulation of amyloid-{beta} (A{beta}) peptides, which are a key factor in its pathogenesis. In this study, we present the design and evaluation of {gamma}-amino-L-proline peptides as metabolically stable, cell-penetrating molecules that can modulate amyloidogenic processing. We screened a library of {gamma}-peptides in primary neuronal cultures to determine their effects on endogenous A{beta}1-42 production, cytotoxicity, and {beta}-secretase (BACE1) activity. Comparative analysis of structurally related analogues enabled the identification of molecular features associated with A{beta}-lowering activity, establishing a qualitative structure-activity relationship. Peptide 33 (P33) emerged as a lead candidate, selectively reducing BACE1 activity without significantly inhibiting the homologous enzyme, BACE2. In vitro blood-brain barrier (BBB) assays revealed that P33 exhibits favorable transendothelial permeability. Intraperitoneal administration of P33 in APP/PS1 mice decreased A{beta} levels, reduced amyloid plaque burden, and improved performance in a behavioral recognition task without inducing cytotoxicity or systemic toxicity. These results define cis-{gamma}-amino-L-proline peptides as a bioorganically distinct and modular scaffold for the development of intracellular modulators of A{beta} production. HighlightsO_LI{gamma}LJAminoLJLLJproline peptides as metabolically stable modulators of A{beta} production. C_LIO_LIP33 showed BBB permeability and BACE1 inhibition in primary cortical neurons. C_LIO_LIIn APP/PS1 mice, P33 lowers amyloid burden and improves cognition. C_LIO_LIP33 shows good biocompatibility, supporting its therapeutic potential in AD C_LI

neuroscience↗

bioRxiv2020

CD8+ T cell responses in convalescent COVID-19 individuals target epitopes from the entireSARS-CoV-2 proteome and show kinetics of early differentiation

Characterization of the T cell response in individuals who recover from SARS-CoV-2 infection is critical to understanding its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 COVID-19 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis, humoral and inflammatory responses. 132 distinct SARS-CoV-2-specific CD8+ T cell epitope responses across six different HLAs were detected, corresponding to 52 unique reactivities. T cell responses were directed against several structural and non-structural virus proteins. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem-cell and transitional memory states, subsets, which may be key to developing durable protection.

immunology↗

bioRxiv2019

Host cholesterol dependent activation of VapC12 toxin enriches persister population during Mycobacterium tuberculosis infection

A worldwide increase in the frequency of multidrug-resistant and extensively drug-resistant cases of tuberculosis is mainly due to therapeutic noncompliance associated with a lengthy treatment regimen. Depending on the drug susceptibility profile, the treatment duration can extend from 6 months to 2 years. This protracted regimen is attributed to a supposedly non-replicating and metabolically inert subset of the Mycobacterium tuberculosis (Mtb) population, called persisters. The mechanism underlying stochastic generation and enrichment of persisters is not fully known. We have previously reported that the utilization of host cholesterol is essential for mycobacterial persistence. In this study, we have demonstrated that cholesterol-induced activation of a ribonuclease toxin (VapC12) inhibits translation by targeting proT tRNA in Mtb. This results in cholesterol-specific growth modulation that increases the frequency of the generation of persisters in a heterogeneous Mtb population. Also, a null mutant strain of this toxin ({Delta}vapC12) failed to persist and demonstrated an enhanced growth phenotype in a guinea pig model of Mtb infection. Thus, we have identified a novel strategy through which cholesterol-specific activation of a toxin-antitoxin (TA) module in Mtb enhances persister formation during infection. In addition to identifying the mechanism, the study provides opportunity for targeting persisters, a new paradigm facilitating tuberculosis drug development.

microbiology↗