Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108797 - 108797

Published: Jan. 1, 2025

The traditional model of protein structure determined by the amino acid sequence is today seriously challenged fact that approximately half human proteome made up proteins do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered (IDPs), are involved numerous physiological functions and associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), type 2 diabetes. Targeting these challenging for two reasons: i) we need to preserve their functions, ii) drug design molecular docking possible due lack reliable starting conditions. Faced this challenge, solutions proposed artificial intelligence (AI) such as AlphaFold clearly unsuitable. Instead, suggest an innovative approach consisting mimicking, short synthetic peptides, conformational flexibility IDPs. which call adaptive derived from domains IDPs become structured after interacting ligand. Adaptive peptides designed aim selectively antagonizing harmful effects IDPs, without targeting them directly but through selected ligands, affecting properties. This"target target, arrow" strategy promised open new route discovery currently undruggable proteins.

Language: Английский

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PED in 2024: improving the community deposition of structural ensembles for intrinsically disordered proteins

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D536 - D544

Published: Oct. 30, 2023

Abstract The Protein Ensemble Database (PED) (URL: https://proteinensemble.org) is the primary resource for depositing structural ensembles of intrinsically disordered proteins. This updated version PED reflects advancements in field, denoting a continual expansion with total 461 entries and 538 ensembles, including those generated without explicit experimental data through novel machine learning (ML) techniques. With this significant increment number few yet-unprecedented new entered database, also determined or refined by electron paramagnetic resonance circular dichroism data. In addition, was enriched several features, deposition service, improved user interface, database cross-referencing options integration 3D-Beacons network—all representing efforts to improve FAIRness database. Foreseeably, will keep growing size expanding types accurate fast ML-based generative models coarse-grained simulations. Therefore, among future efforts, priority be given further develop compatible modeled at level.

Language: Английский

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New insights into protein–protein interaction modulators in drug discovery and therapeutic advance

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 5, 2024

Abstract Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered be undruggable targets have become increasingly feasible due the progress that has been made over last two decades rapid technological advances. This work explores influence of innovations on PPI research development. Additionally, diverse strategies for discovering, modulating, characterizing PPIs their corresponding modulators examined with aim presenting a streamlined pipeline advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in modulator discovery development, we illustrate efficacy various identifying, optimizing, overcoming challenges associated design. The valuable lessons insights gained from identification, optimization, approval discussed demonstrating transitioned beyond early-stage now represent prime opportunity significant potential. examples encompass those developed cancer, inflammation immunomodulation, well antiviral applications. perspective aims establish foundation effective targeting modulation using pave way future

Language: Английский

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The roles of intrinsically disordered proteins in neurodegeneration

Biochimica et Biophysica Acta (BBA) - General Subjects, Journal Year: 2025, Volume and Issue: unknown, P. 130772 - 130772

Published: Feb. 1, 2025

Language: Английский

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Exploring chemical space for “druglike” small molecules in the age of AI

Frontiers in Molecular Biosciences, Journal Year: 2025, Volume and Issue: 12

Published: March 17, 2025

The announcement of 2024 Nobel Prize in Chemistry to Alphafold has reiterated the role AI biology and mainly domain "drug discovery". Till few years ago, structure-based drug design (SBDD) been preferred experimental many academic pharmaceutical R D divisions for developing novel therapeutics. However, with advent AI, field especially seen a paradigm shift its R&D across platforms. If design" is game, there are two main players, small molecule target biomolecule, rules governing game based on interactions between these players. In this brief review, we will be discussing our efforts improving state-of-the-art technology respect molecules as well understanding game. review broadly divided into five sections first section introducing challenges faced domain. second section, describe some existing libraries developed labs follow-up more recent knowledge-based resource available public use. four, screening tools laboratories Finally, delves how knowledge utilization design. We provide three case studies from work illustrate work. conclude thoughts future scope

Language: Английский

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Predicting Conformational Ensembles of Intrinsically Disordered Proteins: From Molecular Dynamics to Machine Learning

The Journal of Physical Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(32), P. 8177 - 8186

Published: Aug. 2, 2024

Intrinsically disordered proteins and regions (IDP/IDRs) are ubiquitous across all domains of life. Characterized by a lack stable tertiary structure, IDP/IDRs populate diverse set transiently formed structural states that can promiscuously adapt upon binding with specific interaction partners and/or certain alterations in environmental conditions. This malleability is foundational for their role as tunable hubs core cellular processes such signaling, transcription, translation. Tracing the conformational ensemble an IDP/IDR its perturbation response to regulatory cues thus paramount illuminating function. However, heterogeneity poses several challenges. Here, we review experimental computational methods devised disentangle landscape IDP/IDRs, highlighting recent advances permit proteome-wide scans conformations. We briefly evaluate selected using N-terminal human copper transporter 1 test case outline further challenges prediction.

Language: Английский

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New Approach for Targeting Small Molecule Candidates for Intrinsically Disordered Proteins

Published: April 23, 2025

Intrinsically disordered proteins (IDPs), like the Alzheimer’s associated tau protein, pose challenges for conventional drug discovery. This study applied Informational Spectrum Method Small Molecules (ISM-SM), a computational technique utilising electron-ion interaction potentials (EIIP), to identify potential modulators. Characteristic frequencies derived from known ligands and conserved mammalian sequences were used screen DrugBank COCONUT natural product database. The screening identified approved drugs previously reported indirectly influence pathology or disease pathways, alongside products Bryostatin-14, modulate kinases involved in phosphorylation. These findings suggest ISM-SM can serve as an silico tool candidate small molecules, including repurposed products, with relevance function pathology, complementing other IDP discovery strategies.

Language: Английский

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Nanoplatforms Targeting Intrinsically Disordered Protein Aggregation for Translational Neuroscience Applications

Nanomaterials, Journal Year: 2025, Volume and Issue: 15(10), P. 704 - 704

Published: May 8, 2025

Intrinsically disordered proteins (IDPs), such as tau, beta-amyloid (Aβ), and alpha-synuclein (αSyn), are prone to misfolding, resulting in pathological aggregation propagation that drive neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s (PD). Misfolded IDPs aggregate into oligomers fibrils, exacerbating progression by disrupting cellular functions the central nervous system, triggering neuroinflammation neurodegeneration. Furthermore, aggregated exhibit prion-like behavior, acting seeds released extracellular space, taken up neighboring cells, have a propagating pathology across different regions of brain. Conventional inhibitors, small molecules, peptides, antibodies, face challenges stability blood–brain barrier penetration, limiting their efficacy. In recent years, nanotechnology-based strategies, multifunctional nanoplatforms or nanoparticles, emerged promising tools address these challenges. These leverage tailored designs prevent remodel reduce associated neurotoxicity. This review discusses advances designed target Aβ, αSyn aggregation, with focus on roles reducing We examine critical aspects nanoplatform design, choice material backbone targeting moieties, which influence interactions IDPs. also highlight key mechanisms interaction between inhibit redirect cascade towards nontoxic, off-pathway species, disrupt fibrillar structures soluble forms. further outline future directions for enhancing IDP clearance, achieving spatiotemporal control, improving cell-specific targeting. nanomedicine strategies offer compelling paths forward developing more effective targeted therapies diseases.

Language: Английский

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Intrinsically disordered regions regulate RhlE RNA helicase functions in bacteria

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(13), P. 7809 - 7824

Published: June 14, 2024

Abstract RNA helicases—central enzymes in metabolism—often feature intrinsically disordered regions (IDRs) that enable phase separation and complex molecular interactions. In the bacterial pathogen Pseudomonas aeruginosa, non-redundant RhlE1 RhlE2 helicases share a conserved REC catalytic core but differ C-terminal IDRs. Here, we show how IDR diversity defines RhlE helicase specificity of function. Both IDRs facilitate binding separation, localizing proteins cytoplasmic clusters. However, is more efficient enhancing unwinding, exhibits greater tendency for interacts with RNase E endonuclease, crucial player mRNA degradation. Swapping results chimeric are biochemically active functionally distinct as compared to their native counterparts. The RECRhlE1-IDRRhlE2 chimera improves cold growth rhlE1 mutant, gains interaction affects subset both targets. RECRhlE2-IDRRhlE1 instead hampers at low temperatures absence RhlE1, its detrimental effect linked aberrant droplets. By showing modulate protein activities subcellular localization, our study impact on functional differentiation helicases.

Language: Английский

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Conserved molecular recognition by an intrinsically disordered region in the absence of sequence conservation

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

Intrinsically disordered regions (IDRs) are critical for cellular function yet often appear to lack sequence conservation when assessed by multiple alignments. This raises the question of if and how can be encoded preserved in these despite massive variation. To address this question, we have applied coarse-grained molecular dynamics simulations investigate non-specific RNA binding coronavirus nucleocapsid proteins. Coronavirus proteins consist interspersed folded domains that bind RNA. Here, focus on first two proteins: N-terminal domain (NTD) (RBD). While NTD is highly variable across evolution, RBD structurally conserved. combination makes NTD-RBD a convenient model system exploring interplay between an IDR adjacent changes influence recognition partner. Our results reveal surprising degree sequence-specificity both composition precise order amino acids NTD. The presence – depending either suppress or enhance binding. Despite sensitivity, large-scale variation sequences possible while certain features retained. Consequently, conformationally-conserved dynamic RNA:protein complex found protein orthologs surface chemistry. Taken together, insights shed light ability preserve functional characteristics their variability.

Language: Английский

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