Dataset Information

Integrating artificial intelligence-based epitope prediction in a SARS-CoV-2 antibody discovery pipeline: caution is warranted.

ABSTRACT:

Background

SARS-CoV-2-neutralizing antibodies (nABs) showed great promise in the early phases of the COVID-19 pandemic. The emergence of resistant strains, however, quickly rendered the majority of clinically approved nABs ineffective. This underscored the imperative to develop nAB cocktails targeting non-overlapping epitopes.

Methods

Undertaking a nAB discovery program, we employed a classical workflow, while integrating artificial intelligence (AI)-based prediction to select non-competing nABs very early in the pipeline. We identified and in vivo validated (in female Syrian hamsters) two highly potent nABs.

Findings

Despite the promising results, in depth cryo-EM structural analysis demonstrated that the AI-based prediction employed with the intention to ensure non-overlapping epitopes was inaccurate. The two nABs in fact bound to the same receptor-binding epitope in a remarkably similar manner.

Interpretation

Our findings indicate that, even in the Alphafold era, AI-based predictions of paratope-epitope interactions are rough and experimental validation of epitopes remains an essential cornerstone of a successful nAB lead selection.

Funding

Full list of funders is provided at the end of the manuscript.

SUBMITTER: Acar DD

PROVIDER: S-EPMC10803917 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Integrating artificial intelligence-based epitope prediction in a SARS-CoV-2 antibody discovery pipeline: caution is warranted.

Acar Delphine Diana DD Witkowski Wojciech W Wejda Magdalena M Wei Ruifang R Desmet Tim T Schepens Bert B De Cae Sieglinde S Sedeyn Koen K Eeckhaut Hannah H Fijalkowska Daria D Roose Kenny K Vanmarcke Sandrine S Poupon Anne A Jochmans Dirk D Zhang Xin X Abdelnabi Rana R Foo Caroline S CS Weynand Birgit B Reiter Dirk D Callewaert Nico N Remaut Han H Neyts Johan J Saelens Xavier X Gerlo Sarah S Vandekerckhove Linos L

EBioMedicine 20240116

<h4>Background</h4>SARS-CoV-2-neutralizing antibodies (nABs) showed great promise in the early phases of the COVID-19 pandemic. The emergence of resistant strains, however, quickly rendered the majority of clinically approved nABs ineffective. This underscored the imperative to develop nAB cocktails targeting non-overlapping epitopes.<h4>Methods</h4>Undertaking a nAB discovery program, we employed a classical workflow, while integrating artificial intelligence (AI)-based prediction to select non ...[more]

PMID: 38232633

Similar Datasets

Project description:BackgroundIdentifying the behavioral state for wild animals that can't be directly observed is of growing interest to the ecological community. Advances in telemetry technology and statistical methodologies allow researchers to use space-use and movement metrics to infer the underlying, latent, behavioral state of an animal without direct observations. For example, researchers studying ungulate ecology have started using these methods to quantify behaviors related to mating strategies. However, little work has been done to determine if assumed behaviors inferred from movement and space-use patterns correspond to actual behaviors of individuals.MethodsUsing a dataset with male and female white-tailed deer location data, we evaluated the ability of these two methods to correctly identify male-female interaction events (MFIEs). We identified MFIEs using the proximity of their locations in space as indicators of when mating could have occurred. We then tested the ability of utilization distributions (UDs) and hidden Markov models (HMMs) rendered with single sex location data to identify these events.ResultsFor white-tailed deer, male and female space-use and movement behavior did not vary consistently when with a potential mate. There was no evidence that a probability contour threshold based on UD volume applied to an individual's UD could be used to identify MFIEs. Additionally, HMMs were unable to identify MFIEs, as single MFIEs were often split across multiple states and the primary state of each MFIE was not consistent across events.ConclusionsCaution is warranted when interpreting behavioral insights rendered from statistical models applied to location data, particularly when there is no form of validation data. For these models to detect latent behaviors, the individual needs to exhibit a consistently different type of space-use and movement when engaged in the behavior. Unvalidated assumptions about that relationship may lead to incorrect inference about mating strategies or other behaviors.

Project description:Antimalarial drugs are becoming less effective due to the emergence of drug resistance. Resistance has been reported for all available malaria drugs, including artemisinin, thus creating a perpetual need for alternative drug candidates. The traditional drug discovery approach of high throughput screening (HTS) of large compound libraries for identification of new drug leads is time-consuming and resource intensive. While virtual in silico screening is a solution to this problem, however, the generalization of the models is not ideal. Artificial intelligence (AI), utilizing either structure-based or ligand-based approaches, has demonstrated highly accurate performances in the field of chemical property prediction. Leveraging the existing data, AI would be a suitable alternative to blind-search HTS or fingerprint-based virtual screening. The AI model would learn patterns within the data and help to search for hit compounds efficiently. In this work, we introduce DeepMalaria, a deep-learning based process capable of predicting the anti-Plasmodium falciparum inhibitory properties of compounds using their SMILES. A graph-based model is trained on 13,446 publicly available antiplasmodial hit compounds from GlaxoSmithKline (GSK) dataset that are currently being used to find novel drug candidates for malaria. We validated this model by predicting hit compounds from a macrocyclic compound library and already approved drugs that are used for repurposing. We have chosen macrocyclic compounds as these ligand-binding structures are underexplored in malaria drug discovery. The in silico pipeline for this process also consists of additional validation of an in-house independent dataset consisting mostly of natural product compounds. Transfer learning from a large dataset was leveraged to improve the performance of the deep learning model. To validate the DeepMalaria generated hits, we used a commonly used SYBR Green I fluorescence assay based phenotypic screening. DeepMalaria was able to detect all the compounds with nanomolar activity and 87.5% of the compounds with greater than 50% inhibition. Further experiments to reveal the compounds' mechanism of action have shown that not only does one of the hit compounds, DC-9237, inhibits all asexual stages of Plasmodium falciparum, but is a fast-acting compound which makes it a strong candidate for further optimization.

Project description:Aptamers are short single-stranded DNA, RNA, or synthetic Xeno nucleic acids (XNA) molecules that can interact with corresponding targets with high affinity. Owing to their unique features, including low cost of production, easy chemical modification, high thermal stability, reproducibility, as well as low levels of immunogenicity and toxicity, aptamers can be used as an alternative to antibodies in diagnostics and therapeutics. Systematic evolution of ligands by exponential enrichment (SELEX), an experimental approach for aptamer screening, allows the selection and identification of in vitro aptamers with high affinity and specificity. However, the SELEX process is time consuming and characterization of the representative aptamer candidates from SELEX is rather laborious. Artificial intelligence (AI) could help to rapidly identify the potential aptamer candidates from a vast number of sequences. This review discusses the advancements of AI pipelines/methods, including structure-based and machine/deep learning-based methods, for predicting the binding ability of aptamers to targets. Structure-based methods are the most used in computer-aided drug design. For this part, we review the secondary and tertiary structure prediction methods for aptamers, molecular docking, as well as molecular dynamic simulation methods for aptamer-target binding. We also performed analysis to compare the accuracy of different secondary and tertiary structure prediction methods for aptamers. On the other hand, advanced machine-/deep-learning models have witnessed successes in predicting the binding abilities between targets and ligands in drug discovery and thus potentially offer a robust and accurate approach to predict the binding between aptamers and targets. The research utilizing machine-/deep-learning techniques for prediction of aptamer-target binding is limited currently. Therefore, perspectives for models, algorithms, and implementation strategies of machine/deep learning-based methods are discussed. This review could facilitate the development and application of high-throughput and less laborious in silico methods in aptamer selection and characterization.

Dataset Information

Integrating artificial intelligence-based epitope prediction in a SARS-CoV-2 antibody discovery pipeline: caution is warranted.

Background

Methods

Findings

Interpretation

Funding

Publications

Integrating artificial intelligence-based epitope prediction in a SARS-CoV-2 antibody discovery pipeline: caution is warranted.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets