Microbiological Research, Journal Year: 2024, Volume and Issue: 292, P. 128025 - 128025
Published: Dec. 16, 2024
Language: Английский
Chemical Communications, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 1, 2025
A small molecular adapter enables site-specific peptide–protein conjugation via cysteine modification and cyanopyridine–aminothiol reactions, yielding complex branched or cyclic architectures for potential protein therapeutics.
Language: Английский
Citations
0
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: Dec. 23, 2024
Abstract Mirror-image proteins, composed of d -amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development mirror-image binding proteins is achieved through chemical synthesis -target phage display library selection l -binders (mirror-image) that consequently bind the physiological -targets. Monobodies well-established synthetic ( -)binding their small size (~90 residues) endogenous cysteine residues make them particularly accessible to synthesis. Here, we develop monobodies with nanomolar affinities against -SH2 domain leukemic tyrosine kinase BCR::ABL1. Two crystal structures heterochiral monobody-SH2 complexes reveal targeting pY pocket by unconventional mode. We then prepare potent -monobodies either ligating two chemically synthesized -peptides or self-assembly without ligation. Their proper folding determined high-affinity shown. protease-resistant, show long-term plasma stability, inhibit BCR::ABL1 activity in cell lysates permeabilized cells. Hence, demonstrate functional can be developed readily. Our work represents important step towards possible future use when combined emerging methods enable cytoplasmic delivery monobodies.
Language: Английский
Citations
1
Chem & Bio Engineering, Journal Year: 2024, Volume and Issue: 2(3), P. 132 - 155
Published: Dec. 23, 2024
Proteins are an important therapeutic modality in modern medicine. However, their inherent inability to traverse cell membranes essentially limits application extracellular targets. Recent advances intracellular protein delivery have enabled access traditionally "undruggable" targets and paved the way precisely modulate cellular functions. This Review provides a comprehensive examination of key mechanisms emerging technologies that facilitate transport functional proteins across membranes. Delivery methods categorized into physical, chemical, biological approaches, each with distinct advantages limitations. Physical enable direct entry but often pose challenges related invasiveness technical complexity. Chemical strategies offer customizable solutions enhanced control over targeting uptake, yet may face issues cytotoxicity scalability. Biological approaches leverage naturally occurring processes achieve efficient transport, though regulatory production consistency remain hurdles. By highlighting recent advancements, challenges, opportunities within approach, this review underscores potential unlock new pathways transform drug development paradigms.
Language: Английский
Citations
1
Microbiological Research, Journal Year: 2024, Volume and Issue: 292, P. 128025 - 128025
Published: Dec. 16, 2024
Language: Английский
Citations
0