A general temperature-guided language model to design proteins of enhanced stability and activity

Science Advances, Journal Year: 2024, Volume and Issue: 10(48)

Published: Nov. 27, 2024

Designing protein mutants with both high stability and activity is a critical yet challenging task in engineering. Here, we introduce PRIME, deep learning model, which can suggest improved without any prior experimental mutagenesis data for the specified protein. Leveraging temperature-aware language modeling, PRIME demonstrated superior predictive ability compared to current state-of-the-art models on public dataset across 283 assays. Furthermore, validated PRIME’s predictions five proteins, examining impact of top 30 45 single-site mutations various properties, including thermal stability, antigen-antibody binding affinity, polymerize nonnatural nucleic acid or resilience extreme alkaline conditions. More than 30% PRIME-recommended exhibited performance their premutation counterparts all proteins desired properties. We developed an efficient effective method based rapidly obtain multisite enhanced stability. Hence, demonstrates broad applicability

Language: Английский

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Appraisal terpenoids rich Boswellia carterri ethyl acetate extract in binary cyclodextrin oligomer nano complex for improving respiratory distress

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 22, 2024

Boswellia carterii (BC) resins plants have a long historical background as treatment for inflammation, indicated by information originating from multiple countries. Twenty-seven diterpenoids been identified in ethyl acetate and total methanol BC, comprising seventeen boscartins of the cembrane-type ten boscartols prenylaromadendrane-type diterpenoids. Moreover, twenty-one known triterpenoids also found, encompassing nine tirucallane-type, six ursane-type, four oleanane-type, two lupane-type. The hold significant position pharmaceutical chemistry related industries due to their captivating biological characteristics promising pharmacological potentials. Extraction creation assessment nano sponges loaded with either B. plant extract or DEX, are subjects our current investigation. With use ultrasound-assisted synthesis, were produced. entrapment efficiency (EE%) medications was examined using spectrophotometry. Nano characterized number methods. Within sponges, EE% medicines varied between 98.52 ± 0.07 99.64 1.40%. sponges' particle sizes 105.9 15.9 166.8 26.3 nm. Drugs released Korsmeyer-Peppas concept. In respiratory distressed rats, effects BC extract, DEX salt formulations (D1, D5, P1 P1), tested. Treatment significantly reduced ICAM-1, LTB4, ILβ 4 levels improved histopathologic profiles, when compared positive control group. its sponge formulation showed therapeutic effects. effect may be synergism both formulation. This achieved blocking ICAM-1 LTB4 pathways, therefore counteracting talc powder.

Language: Английский

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siRNA-Encapsulated Biomimetic Liposomes Effectively Inhibit Tumor Cells’ Hexosamine Biosynthesis Pathway for Attenuating Hyaluronan Barriers to Pancreatic Cancer Chemotherapy

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to excessive hyaluronic acid (HA) accumulation, which impedes drug delivery. Here, we present a targeted approach reduce HA production by specifically silencing glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), key enzyme of the hexosamine biosynthesis pathway (HBP) in pancreatic cancer cells. An engineered liposomal system for siGFAT1 delivery, PMLip@siGFAT1, characterized macrophage membrane camouflage, LFC131 peptide-mediated targeting, and calcium phosphate (CaP) as core, was designed ensure prolonged circulation, enhanced inflamed vascular endothelial penetration, subsequent effective tumor cell uptake endosomal escape. Consequently, PMLip@siGFAT1 markedly downregulated level PDAC microenvironment, decompressing vasculature weakening stromal barrier, turn improved permeability chemotherapeutics. In combination with Doxil, demonstrated potent antitumor efficacy minimal systemic toxicity. Importantly, unlike PEGPH20 (hyaluronidase), reduced invasiveness, while preserving skeletal muscle integrity. These findings highlight that holds great potential revitalize downregulation strategies delivery efficacy.

Language: Английский

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Pure drug nanomedicines - where we are?

Chinese Journal of Natural Medicines, Journal Year: 2025, Volume and Issue: 23(4), P. 385 - 409

Published: April 1, 2025

Language: Английский

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Trimeric Bet v 1-specific nanobodies cause strong suppression of IgE binding

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 3, 2024

Background Around 20% of the population in Northern and Central Europe is affected by birch pollen allergy, with major allergen Bet v 1 as main elicitor allergic reactions. Together its cross-reactive allergens from related trees foods, causes an impaired quality life. Hence, new treatment strategies were elaborated, demonstrating effectiveness blocking IgG antibodies on 1-induced IgE-mediated A recent study provided evidence for first time that 1-specific nanobodies reduce patients´ IgE binding to 1. In order increase potential outcompete recognition foster cross-reactivity cross-protection, we developed nanobody trimers evaluated their capacity suppress polyclonal corresponding allergen-induced basophil degranulation. Methods Nanobody engineered adding isoleucine zippers, thus enabling trimeric formation. Trimers analyzed cross-reactivity, kinetics 1, allergens, patients’ inhibition potential. Finally, efficacy prevent degranulation was investigated. Results showed enhanced increased efficiency IgE-allergen compared monomers. Furthermore, displayed slow dissociation rates suppressed mediator release. Conclusion We generated high-affine target allergens. blocked interaction competing binding. They inhibited release biological mediators, a promising reactions caused relatives.

Language: Английский

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Extract-Shaped Immune Repertoires as Source for Nanobody-Based Human IgE in Grass Pollen Allergy

Molecular Biotechnology, Journal Year: 2023, Volume and Issue: 65(9), P. 1518 - 1527

Published: Jan. 25, 2023

Language: Английский

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Molecular engineering of nanobodies as tools in allergology: diagnostics and beyond

Allergo Journal International, Journal Year: 2023, Volume and Issue: 32(7), P. 240 - 250

Published: July 13, 2023

Language: Английский

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Cell-based in vitro models for nasal permeability studies

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 109 - 135

Published: Jan. 1, 2024

Language: Английский

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Extending Linker Sequences between Antigen-Recognition Modules Provides More Effective Production of Bispecific Nanoantibodies in the Periplasma of E. coli

Biochemistry (Moscow), Journal Year: 2024, Volume and Issue: 89(5), P. 933 - 941

Published: May 1, 2024

Language: Английский

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Effect of enclosing terpenoids-rich Boswellia Carterri ethyl acetate extract in binary cyclodextrin based oligomer nano-complex for improving its activity via counteracting ICAM-1, Ilβ4 and LTB4 pathways in respiratory distressed rats

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

Published: Jan. 8, 2024

Boswellia carterii (BC) resins plants have a long historical background as treatment for inflammation, indicated by information originating from multiple countries. Twenty-seven diterpenoids been identified in ethylacetate and total methanol BC, comprising seventeen boscartins of the cembrane-type ten boscartols prenylaromadendrane-type diterpenoids. Moreover, twenty-one known triterpenoids also found, encompassing nine tirucallane-type, six ursane-type, four oleanane-type, two lupane-type. The hold significant position pharmaceutical chemistry related industries due to their captivating biological characteristics promising pharmacological potentials. Extraction creation assessment nano sponges loaded with either B. Carterii plant extract or DEX, are subjects our current investigation. With use ultrasound-assisted synthesis, were produced. entrapment efficiency (EE%) medications Nano was examined using spectrophotometry. characterized number methods. Within sponges, EE% medicines varied between 98.52± 0.07 99.64± 1.40%. sponges' particle sizes 105.9±15.9 166.8±26.3 nm. Drugs released Korsmeyer-Peppas concept. In respiratory distressed rats, effects BC extract, DEX salt formulations (D1, D5, P1 P1), tested. Treatment significantly reduced ICAM-1, LTB4, ILβ4 levels improved histopathologic profiles, when compared positive control group. Boswellia its sponge formulation showed therapeutic effects. effect may be synergism both formulation. This achieved blocking ICAM-1 LTB4 pathways, therefore counteracting talc powder.

Language: Английский

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