Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation DOI Creative Commons

Justin H. Faris,

Emel Adaligil,

Nataliya Popovych

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(7), P. 4582 - 4591

Published: Feb. 8, 2024

The effort to modulate challenging protein targets has stimulated interest in ligands that are larger and more complex than typical small-molecule drugs. While combinatorial techniques such as mRNA display routinely produce high-affinity macrocyclic peptides against classically undruggable targets, poor membrane permeability limited their use toward primarily extracellular targets. Understanding the passive of would, principle, improve our ability design libraries whose leads can be readily optimized intracellular Here, we investigate permeabilities over 200 10-mers using thioether cyclization motif commonly found macrocycle libraries. We identified optimal lipophilicity range for achieving thioether-cyclized 10-mer cyclic peptide-peptoid hybrid scaffolds showed could maintained upon extensive permutation backbone. In one case, changing a single amino acid from d-Pro d-NMe-Ala, representing loss methylene group side chain, resulted highly permeable scaffold which low-dielectric conformation shifted canonical cross-beta geometry parent compounds into novel saddle-shaped fold all four backbone NH groups were sequestered solvent. This work provides an example by pre-existing physicochemical knowledge benefit peptide libraries, pointing approach biasing design. Moreover, described herein further demonstration geometrically diverse, exist well beyond conventional drug-like chemical space.

Language: Английский

Cyclic Peptides for Drug Development DOI Creative Commons
Xinjian Ji, Alexander L. Nielsen, Christian Heinis

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 63(3)

Published: Oct. 23, 2023

Abstract Cyclic peptides are fascinating molecules abundantly found in nature and exploited as molecular format for drug development well other applications, ranging from research tools to food additives. Advances peptide technologies made over many years through improved methods synthesis have resulted a steady stream of new drugs, with an average around one cyclic approved per year. Powerful screening random libraries, de novo generating ligands, enabled the drugs independent naturally derived now offer virtually unlimited opportunities. In this review, we feature therapeutically relevant discuss unique properties peptides, enormous technological advances ligand recent years, current challenges opportunities developing that address unmet medical needs.

Language: Английский

Citations

150
Macrocycles in Drug Discovery─Learning from the Past for the Future DOI Creative Commons
Diego García Jiménez, Vasanthanathan Poongavanam, Jan Kihlberg

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(8), P. 5377 - 5396

Published: April 5, 2023

We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs mainly infectious disease oncology, while oncology is major indication for candidates Most bind targets that difficult binding sites. Natural products provided 80–90% of whereas ChEMBL less complex structures. Macrocycles usually reside beyond Rule 5 chemical space, but 30–40% orally bioavailable. Simple bi-descriptor models, i.e., HBD ≤ 7 combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals can be as filters design. propose breakthroughs conformational analysis inspiration natural will further improve de novo design macrocycles.

Language: Английский

Citations

135
Cyclic peptide structure prediction and design using AlphaFold DOI Creative Commons
Stephen Rettie, Katelyn V. Campbell, Asim K. Bera

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 26, 2023

ABSTRACT Deep learning networks offer considerable opportunities for accurate structure prediction and design of biomolecules. While cyclic peptides have gained significant traction as a therapeutic modality, developing deep methods designing such has been slow, mostly due to the small number available structures molecules in this size range. Here, we report approaches modify AlphaFold network peptides. Our results show approach can accurately predict native from single sequence, with 36 out 49 cases predicted high confidence (pLDDT > 0.85) matching root mean squared deviation (RMSD) less than 1.5 Å. Further extending our approach, describe computational sequences peptide backbones generated by other backbone sampling de novo new macrocyclic We extensively sampled structural diversity between 7–13 amino acids, identified around 10,000 unique candidates fold into designed confidence. X-ray crystal seven diverse sizes match very closely models (root < 1.0 Å), highlighting atomic level accuracy approach. The scaffolds developed here provide basis custom-designing targeted applications.

Language: Английский

Citations

46
Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets DOI

Atsushi Ohta,

Mikimasa Tanada,

Shojiro Shinohara

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(44), P. 24035 - 24051

Published: Oct. 24, 2023

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they not suitable target protein that lacks deep cavity molecule bind or found in space out of an antibody's reach. One possible approach access these targets is utilize so-called middle-size cyclic peptides (defined here as those with molecular weight 1000-2000 g/mol). In this study, we validated new methodology create oral drugs beyond rule 5 tough by elucidating structural features physicochemical properties drug-like developing library technologies afford highly N-alkylated peptide hits. We discovered KRAS inhibitory compound (LUNA18) first example our technology.

Language: Английский

Citations

45
De novo development of small cyclic peptides that are orally bioavailable DOI Creative Commons
Manuel L. Merz, Sevan Habeshian, Bo Li

et al.

Nature Chemical Biology, Journal Year: 2023, Volume and Issue: 20(5), P. 624 - 633

Published: Dec. 28, 2023

Cyclic peptides can bind challenging disease targets with high affinity and specificity, offering enormous opportunities for addressing unmet medical needs. However, as biological drugs, most cyclic cannot be applied orally because they are rapidly digested and/or display low absorption in the gastrointestinal tract, hampering their development therapeutics. In this study, we developed a combinatorial synthesis screening approach based on sequential cyclization one-pot peptide acylation screening, possibility of simultaneously interrogating activity permeability. proof concept, synthesized library 8,448 screened them against target thrombin. Our workflow allowed multiple iterative cycles yielded nanomolar affinities, stabilities an oral bioavailability (%F) 18% rats. This method generating available is general provides promising push toward unlocking full potential

Language: Английский

Citations

45
AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery DOI Creative Commons
Yue Xu,

Shihao Ma,

Haotian Cui

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 26, 2024

Abstract Ionizable lipid nanoparticles (LNPs) are seeing widespread use in mRNA delivery, notably SARS-CoV-2 vaccines. However, the expansion of therapies beyond COVID-19 is impeded by absence LNPs tailored for diverse cell types. In this study, we present AI-Guided Lipid Engineering (AGILE) platform, a synergistic combination deep learning and combinatorial chemistry. AGILE streamlines ionizable development with efficient library design, silico screening via neural networks, adaptability to lines. Using AGILE, rapidly synthesize, evaluate lipids selecting from vast library. Intriguingly, reveals cell-specific preferences lipids, indicating tailoring optimal delivery varying These highlight AGILE’s potential expediting customized LNPs, addressing complex needs clinical practice, thereby broadening scope efficacy therapies.

Language: Английский

Citations

24
Expansive discovery of chemically diverse structured macrocyclic oligoamides DOI
Patrick J. Salveson, Adam Moyer, Meerit Y. Said

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6694), P. 420 - 428

Published: April 25, 2024

Small macrocycles with four or fewer amino acids are among the most potent natural products known, but there is currently no way to systematically generate such compounds. We describe a computational method for identifying ordered composed of alpha, beta, gamma, and 17 other acid backbone chemistries, which we used predict 14.9 million closed cycles >42,000 monomer combinations. chemically synthesized 18 predicted adopt single low-energy states determined their x-ray nuclear magnetic resonance structures; 15 these were very close design models. illustrate therapeutic potential macrocycle designs by developing selective inhibitors three protein targets current interest. By opening up vast space readily synthesizable drug-like macrocycles, our results should considerably enhance structure-based drug design.

Language: Английский

Citations

20
Peptide-Aware Chemical Language Model Successfully Predicts Membrane Diffusion of Cyclic Peptides DOI
Aaron L. Feller, Claus O. Wilke

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language modeling applied to biological data has significantly advanced the prediction of membrane penetration for small-molecule drugs and natural peptides. However, accurately predicting diffusion peptides with pharmacologically relevant modifications remains a substantial challenge. Here, we introduce PeptideCLM, peptide-focused chemical language model capable encoding modifications, unnatural or noncanonical amino acids, cyclizations. We assess this by cyclic peptides, demonstrating greater predictive power than existing models. Our is versatile can be extended beyond predictions other target values. Its advantages include ability macromolecules using string notation, largely unexplored domain, simple, flexible architecture that allows adaptation any peptide macromolecule set.

Language: Английский

Citations

2
Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers DOI
James Cregg, Kristóf Póta, Aidan C.A. Tomlinson

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

The discovery of elironrasib (RMC-6291) represents a significant breakthrough in targeting the previously deemed undruggable GTP-bound, active KRASG12C. To target state RAS (RAS(ON)) directly, we have employed an innovative tri-complex inhibitor (TCI) modality involving formation complex with inhibitor, intracellular chaperone protein CypA, and KRASG12C its GTP-bound form. resulting inhibits oncogenic signaling, inducing tumor regressions across various preclinical models mutant human cancers. Here report structure-guided medicinal chemistry efforts that led to elironrasib, potent, orally bioavailable, RAS(ON) G12C-selective, covalent, inhibitor. investigational agent is currently undergoing phase 1 clinical trials (NCT05462717, NCT06128551, NCT06162221), preliminary data indicating activity patients who had progressed on first-generation inactive state-selective inhibitors.

Language: Английский

Citations

2
Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines DOI Creative Commons
Wen‐Jing Xiao, Wenjie Jiang, Zheng Chen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 5, 2025

The successful approval of peptide-based drugs can be attributed to a collaborative effort across multiple disciplines. integration novel drug design and synthesis techniques, display library technology, delivery systems, bioengineering advancements, artificial intelligence have significantly expedited the development groundbreaking drugs, effectively addressing obstacles associated with their character, such as rapid clearance degradation, necessitating subcutaneous injection leading increasing patient discomfort, ultimately advancing translational research efforts. Peptides are presently employed in management diagnosis diverse array medical conditions, diabetes mellitus, weight loss, oncology, rare diseases, additionally garnering interest facilitating targeted platforms advancement vaccines. This paper provides an overview present market clinical trial progress therapeutics, platforms, It examines key areas through literature analysis emphasizes structural modification principles well recent advancements screening, design, technologies. accelerated including peptide-drug complexes, new vaccines, innovative diagnostic reagents, has potential promote era precise customization disease therapeutic schedule.

Language: Английский

Citations

2