Biology subjects

Martinez Cuesta, S.

Publications and source records attributed to Martinez Cuesta, S..

4 recordsLinked to original sources

bioRxiv2026

Combinatorial screening of biological degrader modules identifies heterobifunctional molecules that efficiently destroy MYC, leading to rapid tumour cell death in vitro and in vivo

Targeted protein degradation is a potent strategy against intracellular proteins impervious to traditional drugs. We describe a platform reliant on high-throughput cloning and mRNA-based delivery to quickly screen 100s-1000s of modular biological degraders, which we challenge against the high-turnover c-Myc oncoprotein. We uncover critical principles to drive degrader discovery against any target, free from tagging or prior cell line engineering, with direct applications in research and potentially therapy. We demonstrate the feasibility of targeted protein degradation of c-Myc across in vitro cancer models and in vivo xenograft model, uncovering distinct cellular responses between c-Myc degradation and inhibition.

bioengineering↗

bioRxiv2025

Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design

Molecular glues are small molecules that offer a powerful strategy to target previously "undruggable" proteins of interest (POI) by enhancing their interactions with other proteins (effector). Depending on the nature of the effectors, molecular glues can induce stabilizing sequestration or degradation of POI. However, their rational design has been hindered by a poor understanding of how kinetic parameters impact their performance. To address this, we developed a unified mathematical framework that accurately analyzes the dynamics of both glue degraders and stabilizers. Our model reveals that the strong binding affinity of the ternary complex is the key determinant of performance across both modalities, provided that the initial component concentrations and degradation rate constants are fixed. Furthermore, we demonstrate that degrader performance is ultimately limited by its catalytic efficiency and the target proteins natural half-life. We also identify distinct roles for effector abundance, showing that the relative concentrations of the effector and POI are critical for stabilizers but less so for degraders. This quantitative framework provides mechanistic principles for the rationale design and optimization of molecular glues.

molecular biology↗

bioRxiv2025

RP3Net: a deep learning model for predicting recombinant protein production in Escherichia coli

Recombinant protein expression can be a limiting step in the production of protein reagents for drug discovery and other biotechnology applications. We introduce RP3Net (Recombinant Protein Production Prediction Network), an AI model of small-scale heterologous soluble protein expression in Escherichia coli. RP3Net utilizes the most recent protein and genomic foundational models. A curated dataset of internal experimental results from AstraZeneca (AZ) and publicly available data from the Structural Genomics Consortium (SGC) was used for training, validation and testing of RP3Net. Set Transformer Pooling (STP) aggregation and Meta Label Correction (MLC) with large scale purification data enabled RP3Net to improve Area Under Receiver Operator Curve (AUROC) by 0.15, compared to the baseline model. When experimentally validated on an independent, manually selected set of 97 constructs, RP3Net outperformed currently available models, with an AUROC of 0.83, delivering accurate predictions in 77% of the cases, and correctly identifying successfully expressing constructs in 92% of cases.

bioinformatics↗

bioRxiv2017

5-Formylcytosine controls nucleosome positioning through covalent histone-DNA interaction

Nucleosomes are the basic unit of chromatin that ensure genome integrity and control access to the genetic information. The organization of nucleosomes is influenced by the underlying DNA sequence itself, transcription factors or other transcriptional machinery associated proteins and chromatin remodeling complexes (1-4). Herein, we show that the naturally occurring DNA modification, 5-formylcytosine (5fC) contributes to the positioning of nucleosomes. We show that the ability of 5fC to position nucleosomes in vitro is associated with the formation of covalent interactions between histone residues and 5fC in the form of Schiff bases. We demonstrate that similar interactions can occur in a cellular environment and define their specific genomic loci in mouse embryonic stem cells. Collectively, our findings identify 5fC as a determinant of nucleosomal organization in which 5fC plays a role in establishing distinct regulatory regions that are linked to gene expression Our study provides a previously unknown molecular mechanism, involving the formation of reversible-covalent bonds between chromatin and DNA that supports a molecular linkage between DNA sequence, DNA base modification and chromatin structure.

genomics↗