DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors

Protein Engineering Design and Selection, Год журнала: 2024, Номер 37

Опубликована: Янв. 1, 2024

Abstract With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role modulating polarization, signaling, and trafficking pathways. Mutations lead to diseases such as cancer cystic fibrosis, making attractive targets for therapeutic intervention. D-peptide inhibitors offer advantages therapeutics, including increased metabolic stability low immunogenicity. Here, we introduce DexDesign, novel OSPREY-based algorithm computationally designing de novo inhibitors. DexDesign leverages three techniques that are broadly applicable computational protein design: Minimum Flexible Set, K*-based Mutational Scan, Inverse Alanine Scan. We apply these generate of two biomedically important domain targets: CAL MAST2. framework analyzing peptides—evaluation along replication/restitution axis—and it DexDesign-generated D-peptides. Notably, peptides generated predicted bind their tighter than targets' endogenous ligands, validating peptides' potential also provide an implementation free open source design software OSPREY.

Язык: Английский

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Enantioseparation of six profenoid drugs by capillary electrophoresis with bovine serum albumin-modified gold nanoparticles as quasi-stationary phases

Journal of Chromatography B, Год журнала: 2024, Номер 1243, С. 124228 - 124228

Опубликована: Июль 2, 2024

Язык: Английский

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A Snake Venom Peptide and Its Derivatives Prevent Aβ₄₂ Aggregation and Eliminate Toxic Aβ₄₂ Aggregates In Vitro

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(14), С. 2600 - 2611

Опубликована: Июль 3, 2024

Over a century has passed since Alois Alzheimer first described Alzheimer's disease (AD), and then, researchers have made significant strides in understanding its pathology. One key feature of AD is the presence amyloid-β (Aβ) peptides, which form amyloid plaques, therefore, it primary target for treatment studies. Naturally occurring peptides garnered attention their potential pharmacological benefits, particularly central nervous system. In this study, nine peptide derivatives Crotamine, polypeptide from Crotalus durissus terrificus Rattlesnake venom, as well one d-enantiomer, were evaluated ability to modulate Aβ42 aggregation through various assays such ThT, QIAD, SPR, sFIDA. All tested able decrease eliminate aggregates. Additionally, all showed an affinity Aβ42. This study describe crotamine derivative against identify promising d-peptide that could be used effective tool future.

Язык: Английский

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Rapid Production of Native and Mirror-Image Tumor Necrosis Factor-α Enabled by Automated Flow Peptide Synthesis Technology

The Journal of Organic Chemistry, Год журнала: 2024, Номер 89(18), С. 12886 - 12893

Опубликована: Сен. 10, 2024

Tumor necrosis factor-α (TNF-α) plays a central role in immune response regulation. Because elevated TNF-α production is correlated with range of diseases, inhibiting the interaction this protein its native receptors has been thoroughly explored as therapeutic avenue. Despite advancements development inhibitors, concerns remain regarding immunogenicity and loss activity vivo. To facilitate discovery stable less immunogenic modalities, we applied single-shot automated fast-flow peptide synthesis (AFPS) strategy to produce full-length TNF-α, resulting complex reaction mixture. Leveraging ability AFPS generate long peptides high purity, combined technology chemical ligation (NCL). An NCL using two fragments readily produced by afforded synthetic L- D-TNF-α milligram quantities (up 5.5 mg, ∼28% yield). Following oxidative folding established conditions, higher molecular weight species were generated. Through high-throughput screening refolding functional mirror-image obtained, exhibiting characteristics analogous those recombinant TNF-α. Overall, approach can serve general protocol for accessing proteins that are intractable modern methods, therefore, streamlining novel therapeutics.

Язык: Английский

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Enantiomeric histidine-rich peptide coacervates enhance antigen delivery to T cells

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 14, 2024

SUMMARY Peptides and peptidomimetics that self-assemble via LLPS have recently emerged as building blocks for fabricating functional biomaterials due to their unique physicochemical properties dynamic nature. One of life’s most distinctive signatures is its selectivity chiral molecules and, date, coacervates comprised D-amino acids not been reported. Here, we demonstrate histidine-rich repeats (GHGXY) 4 (X=L/V/P) enantiomers undergo opening new avenues enhancing coacervate stability. Through a series biophysical studies, find kinetics, droplet size, fusion, encapsulation efficiency are dictated by the primary sequence. Further, these can encapsulate therapeutic cargo which then internalized endocytic mechanisms. Finally, show enhance antigen presentation CD4 + CD8 T cells resulting in robust proliferation production cytokines. Collectively, our study describes development characterization enantiomeric peptide attractive vaccine delivery vehicles with tunable properties. HIGHLIGHTS D amino acid-peptides were used first time construct phase separating Chirality does restrict or modulate other Antigen using enhances prolongs PROGRESS AND POTENTIAL self-assembly liquid-liquid separation (LLPS) result solute-rich serve biomaterials. Using repeats, this work demonstrates peptides composed entirely form coaceravtes. The kinetics bulk droplets be controlled through simple acid substitutions. coacervates, while immunologically inert, exert an adjuvanting effect leading cytokine production. materials showcased here possess high translational potential combined immunomodulators antigens against infectious diseases cancer. deliverables from will also inspire systems contribute knowledge cellular processes associated changes integral both physiology pathology.

Язык: Английский

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