Arginine Accelerates Sulfur Fluoride Exchange and Phosphorus Fluoride Exchange Reactions between Proteins DOI Creative Commons
Li Cao, Bingchen Yu, Paul C. Klauser

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(47)

Published: Aug. 8, 2024

Abstract Sulfur fluoride exchange (SuFEx) and phosphorus (PFEx) click chemistries are advancing research across multiple disciplines. By genetically incorporating latent bioreactive unnatural amino acids (Uaas), these have been integrated into proteins, enabling precise covalent linkages with biological macromolecules paving the way for new applications. However, their suboptimal reaction rates in proteins limit effectiveness, traditional catalytic methods small molecules often incompatible systems or vivo We demonstrated that introducing an arginine adjacent to Uaa significantly boosts SuFEx PFEx between proteins. This method is effective various Uaas, target residues, protein environments. Notably, it also enables efficient reactions acidic conditions, common certain cellular compartments tumor microenvironments, which typically hinder reactions. Furthermore, we developed first cell engager substantially enhances natural killer activation through improved interaction facilitated by arginine. These findings provide mechanistic insights offer a biocompatible strategy harness robust developing biotherapeutics.

Language: Английский

Biospecific Chemistry for Covalent Linking of Biomacromolecules DOI Creative Commons
Li Cao, Lei Wang

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(13), P. 8516 - 8549

Published: June 24, 2024

Interactions among biomacromolecules, predominantly noncovalent, underpin biological processes. However, recent advancements in biospecific chemistry have enabled the creation of specific covalent bonds between biomolecules, both vitro and vivo. This Review traces evolution proteins, emphasizing role genetically encoded latent bioreactive amino acids. These acids react selectively with adjacent natural groups through proximity-enabled bioreactivity, enabling targeted linkages. We explore various designed to target different protein residues, ribonucleic acids, carbohydrates. then discuss how these novel linkages can drive challenging properties capture transient protein-protein protein-RNA interactions Additionally, we examine application peptides as potential therapeutic agents site-specific conjugates for native antibodies, highlighting their capacity form stable molecules. A significant focus is placed on reactive therapeutics (PERx), a pioneering technology therapeutics. detail its wide-ranging applications immunotherapy, viral neutralization, radionuclide therapy. Finally, present perspective existing challenges within avenues future exploration advancement this rapidly evolving field.

Language: Английский

Citations

11
Strategies to Expand the Genetic Code of Mammalian Cells DOI
Arianna O. Osgood, Zeyi Huang, Kaitlyn H. Szalay

et al.

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Genetic code expansion (GCE) in mammalian cells has emerged as a powerful technology for investigating and engineering protein function. This method allows the precise incorporation of rapidly growing toolbox noncanonical amino acids (ncAAs) into predefined sites target proteins expressed living cells. Due to minimal size these genetically encoded ncAAs, wide range functionalities they provide, ability introduce them freely at virtually any site by simple mutagenesis, this holds immense potential probing complex biology next-generation biotherapeutics. In review, we provide an overview underlying machinery that enables ncAA mutagenesis how are developed. We have also compiled updated list ncAAs been successfully incorporated Finally, our perspectives on current challenges need be addressed fully harness technology.

Language: Английский

Citations

1
Advances in sulfur fluoride exchange for chemical biology DOI
Tobias Hansen,

Marcos San Segundo,

Annika M. Mergel

et al.

Trends in Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Arginine Accelerates Sulfur Fluoride Exchange and Phosphorus Fluoride Exchange Reactions between Proteins DOI Creative Commons
Li Cao, Bingchen Yu, Paul C. Klauser

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(47)

Published: Aug. 8, 2024

Sulfur fluoride exchange (SuFEx) and phosphorus (PFEx) click chemistries are advancing research across multiple disciplines. By genetically incorporating latent bioreactive unnatural amino acids (Uaas), these have been integrated into proteins, enabling precise covalent linkages with biological macromolecules paving the way for new applications. However, their suboptimal reaction rates in proteins limit effectiveness, traditional catalytic methods small molecules often incompatible systems or vivo We demonstrated that introducing an arginine adjacent to Uaa significantly boosts SuFEx PFEx between proteins. This method is effective various Uaas, target residues, protein environments. Notably, it also enables efficient reactions acidic conditions, common certain cellular compartments tumor microenvironments, which typically hinder reactions. Furthermore, we developed first cell engager substantially enhances natural killer activation through improved interaction facilitated by arginine. These findings provide mechanistic insights offer a biocompatible strategy harness robust developing biotherapeutics.

Language: Английский

Citations

3
Sulfur (VI) fluoride exchange (SuFEx): a versatile tool to profile protein-biomolecule interactions for therapeutic development DOI
Lingyun Yang,

Zhengnan Yuan,

Yongkuan Li

et al.

Medicinal Chemistry Research, Journal Year: 2024, Volume and Issue: 33(8), P. 1315 - 1329

Published: June 18, 2024

Language: Английский

Citations

2
P‐F Bond Activation of Organophosphates by [(iPrPNHP)Mn(CO)2]+ DOI
Mario Prejanò,

Marirosa Toscano,

Tiziana Marino

et al.

European Journal of Inorganic Chemistry, Journal Year: 2024, Volume and Issue: 27(34)

Published: Nov. 21, 2024

Abstract Organophosphate compounds (OPC) are chemical species with a broad range of applications from agricultural to medicinal chemistry, which however rose sadly the fore for their use as weapons worldwide. Several efforts therefore carried out contrast toxic effects or repurpose OPC synthesis. In this regard, metal‐containing systems, like metal‐organic frameworks complexes, represent valid solution treatments in number fields. Our work has been inspired by recent findings concerning reactivity ( iPr PN H P)Mn(CO) 2 (OH) 1 ) complex P−F bond containing organophosphate compounds. We, particular, have investigated three different OPC, diisopropylfluorophosphate ), isopropylfluorophosphoric acid b and fluorophosphoric c extending nerve gas sarin sa ). The reaction concerns leaving fluoride produce relative defluorinated phosphates (F) complex. Analysis calculations revealed that is favored both thermodynamic kinetical points view substrate. results agreement available experimental data further confirmation versatility such metal‐complex interact agents.

Language: Английский

Citations

1
Carbene Footprinting Directs Design of Genetically Encoded Proximity-Reactive Protein Binders DOI
Hui Ye,

Yinxue Zhu,

Ying Kong

et al.

Analytical Chemistry, Journal Year: 2024, Volume and Issue: 96(19), P. 7566 - 7576

Published: April 29, 2024

Genetically encoding proximal-reactive unnatural amino acids (PrUaas), such as fluorosulfate-l-tyrosine (FSY), into natural proteins of interest (POI) confer the POI with ability to covalently bind its interacting (IPs). The PrUaa-incorporated POIs hold promise for blocking undesirable POI–IP interactions. Selecting appropriate PrUaa anchor sites is crucial, but it remains challenging current methodology, which heavily relies on crystallography identify proximal residues between and IPs anchorage. To address challenge, here, we propose a footprinting-directed genetically encoded covalent binder (footprinting-GECB) approach. This approach employs carbene footprinting, structural mass spectrometry (MS) technique that quantifies extent labeling following addition IP, thus identifies responsive residues. By these sites, variants bonding IP can be produced without need crystallography. Using model, KRAS/RAF1, showed engineering FSY at footprint-assigned KRAS residue resulted in variant irreversibly RAF1. Additionally, inserted RAF1 upon footprinting oncogenic KRASG12D/RAF1, lacks crystal structure, generated KRASG12D. Together, demonstrated by adopting direct anchorage, greatly expand opportunities designing protein binders PPIs relying holds creating effective PPI inhibitors supports both fundamental research biotherapeutics development.

Language: Английский

Citations

0
Arginine Accelerates Sulfur Fluoride Exchange and Phosphorus Fluoride Exchange Reactions between Proteins DOI Creative Commons
Li Cao, Bingchen Yu, Paul C. Klauser

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(47)

Published: Aug. 8, 2024

Abstract Sulfur fluoride exchange (SuFEx) and phosphorus (PFEx) click chemistries are advancing research across multiple disciplines. By genetically incorporating latent bioreactive unnatural amino acids (Uaas), these have been integrated into proteins, enabling precise covalent linkages with biological macromolecules paving the way for new applications. However, their suboptimal reaction rates in proteins limit effectiveness, traditional catalytic methods small molecules often incompatible systems or vivo We demonstrated that introducing an arginine adjacent to Uaa significantly boosts SuFEx PFEx between proteins. This method is effective various Uaas, target residues, protein environments. Notably, it also enables efficient reactions acidic conditions, common certain cellular compartments tumor microenvironments, which typically hinder reactions. Furthermore, we developed first cell engager substantially enhances natural killer activation through improved interaction facilitated by arginine. These findings provide mechanistic insights offer a biocompatible strategy harness robust developing biotherapeutics.

Language: Английский

Citations

0