Biology subjects

Koch, O.

Publications and source records attributed to Koch, O..

4 recordsLinked to original sources

bioRxiv2026

Modulation of the agonist and antagonist activity of peptidic FPR1 ligands through N-terminal modifications: A structural and functional analysis

Formyl peptide receptor 1 (FPR1) is a promising therapeutic target for the treatment of inflammatory and infectious diseases. Although multiple classes of peptides are known to modulate FPR1 activity, comprehensive studies systematically linking N-terminal modifications to binding, mechanism of action and functional outcomes remain limited. In this study, we aimed to rationalise the binding and activity of three peptide series (MLF, FLFLF, and MLFYLA) featuring diverse N-terminal modifications from a structural point of view. A combined in silico and in vitro approach was employed to evaluate the activity of newly designed peptide agonists and to generate mechanistic binding hypotheses. Our findings led to the identification of a transmembrane binding pocket in FPR1, which provides a structural basis for the observed antagonist and partial agonist behaviours and leads to a generalisable strategy for tuning the functional outcome of peptidic ligands.

pharmacology and toxicology↗

bioRxiv2026

Mutation-Induced Pocket Deactivation: How Ser353/Pro245 Alters KCa2.2 vs KCa3.1 Ligand Selectivity

The KCa2.2 and KCa3.1 channels are fundamental regulator of cellular K+ concentration, and promising target to treat diseases such as spinocerebellar ataxia and cancer. To fully exploit their therapeutic potential, and to continue studying their pathophysiological role, it is crucial to develop selective modulators for each of these two channels. Here we present a computational study to identify the molecular determinants behind the selectivity of two recently reported KCa2.2 modulators. We leveraged a protocol combining in silico mutagenesis, molecular dynamics simulations, and protein-ligand docking to analyse the pockets targeted by these ligands. We identified a Ser353/Pro245 substitution to be the main driver of the distinct pocket shapes in KCa2.2 and KCa3.1 channels, ultimately defining modulator selectivity. This approach provides novel insights into the structural differences of this binding site across potassium channel subtypes, shedding light on the selectivity determinants of modulators targeting this pocket.

pharmacology and toxicology↗

bioRxiv2026

Discovery of the first small-molecule extracellular inhibitor of KCa3.1

The ion channel KCa3.1 plays a role in immune regulation, red blood cell function, and is linked to numerous types of cancer. Various animal toxins, such as maurotoxin, bind to the extracellular side of KCa3.1, providing a potential starting point for inhibitor development. We report in this work the discovery of a novel, small-molecule inhibitor, with a micromolar IC50, which was specifically designed to target plasma-membrane KCa3.1 channels from the extracellular side. This compound can serve as a starting point for the development of more selective inhibitors and probes. For the identification of new extracellular inhibitors, molecular dynamics simulations were performed using the experimental structures of KCa3.1 and maurotoxin. The simulations produced a validated binding mode, highlighting key residues involved in the interaction between the toxin and the channel. These findings laid the foundation for the structure-based identification of novel extracellular small-molecule inhibitors of KCa3.1. The Molport database, containing approximately 50 million compounds, was screened using protein-ligand docking, yielding a hit molecule that was experimentally confirmed using patch clamp assays.

pharmacology and toxicology↗

bioRxiv2021

Modelling potential range expansion of an underutilised food security crop in Sub-Saharan Africa

Despite substantial growth in global agricultural production, food and nutritional insecurity is rising in Sub-Saharan Africa. Identification of underutilised indigenous crops with useful food security traits may provide part of the solution. Enset (Ensete ventricosum) is a perennial banana relative with cultivation restricted to southwestern Ethiopia, where high productivity and harvest flexibility enables it to provide a starch staple for ~20 million people. An extensive wild distribution suggests that a much larger region may be climatically suitable for cultivation. Here we use ensemble ecological niche modelling to predict the potential range for enset cultivation within southern and eastern Africa. We find contemporary bioclimatic suitability for a 12-fold range expansion, equating to 21.9% of crop land and 28.4% of the population in the region. Integration of crop wild relative diversity, which has broader climate tolerance, could enable a 19-fold expansion, particularly to dryer and warmer regions. Whilst climate change may cause a 37% - 52% reduction in potential range by 2070, large centres of suitability remain in the Ethiopian Highlands, Lake Victoria region and the Drakensberg Range. We combine our bioclimatic assessment with socioeconomic data to identify priority areas with high population density, seasonal food deficits and predominantly small-scale subsistence agriculture, where integrating enset may be particularly feasible and deliver climate resilience. When incorporating the genetic potential of wild populations, enset cultivation might prove feasible for an additional 87.2 - 111.5 million people, 27.7 - 33 million of which are in Ethiopia outside of ensets current cultivation range. Finally, we consider explanations why enset cultivation has not expanded historically, and ethical implications of expanding previously underutilised species.

ecology↗