Pub Date : 2024-05-28DOI: 10.1038/s41557-024-01542-9
Chris Torres, Julie E. Rorrer
State-of-the-art plastic deconstruction technologies typically require noble metals, consume hydrogen gas, and generate waste methane. Now it has been shown that earth-abundant layered self-pillared zeolite catalysts selectively convert polyethylene to high-octane products without requiring molecular hydrogen.
{"title":"Layered self-pillared zeolites convert polyethylene to gasoline","authors":"Chris Torres, Julie E. Rorrer","doi":"10.1038/s41557-024-01542-9","DOIUrl":"10.1038/s41557-024-01542-9","url":null,"abstract":"State-of-the-art plastic deconstruction technologies typically require noble metals, consume hydrogen gas, and generate waste methane. Now it has been shown that earth-abundant layered self-pillared zeolite catalysts selectively convert polyethylene to high-octane products without requiring molecular hydrogen.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-24DOI: 10.1038/s41557-024-01520-1
Fabian B. H. Rehm, Tristan J. Tyler, Yan Zhou, Yen-Hua Huang, Conan K. Wang, Nicole Lawrence, David J. Craik, Thomas Durek
Transpeptidases are powerful tools for protein engineering but are largely restricted to acting at protein backbone termini. Alternative enzymatic approaches for internal protein labelling require bulky recognition motifs or non-proteinogenic reaction partners, potentially restricting which proteins can be modified or the types of modification that can be installed. Here we report a strategy for labelling lysine side chain ε-amines by repurposing an engineered asparaginyl ligase, which naturally catalyses peptide head-to-tail cyclization, for versatile isopeptide ligations that are compatible with peptidic substrates. We find that internal lysines with an adjacent leucine residue mimic the conventional N-terminal glycine–leucine substrate. This dipeptide motif enables efficient intra- or intermolecular ligation through internal lysine side chains, minimally leaving an asparagine C-terminally linked to the lysine side chain via an isopeptide bond. The versatility of this approach is demonstrated by the chemoenzymatic synthesis of peptides with non-native C terminus-to-side chain topology and the conjugation of chemically modified peptides to recombinant proteins. Plant asparaginyl endopeptidases that function preferentially as transpeptidases naturally catalyse the head-to-tail cyclization of plant peptides. Using substrate mimicry and reaction optimization, their function has now been repurposed to catalyse intermolecular isopeptide bond formation on diverse peptide and protein substrates.
反肽酶是蛋白质工程的强大工具，但在很大程度上仅限于作用于蛋白质骨架末端。用于蛋白质内部标记的其他酶法需要大体积识别基团或非蛋白源反应伙伴，这可能会限制可修饰的蛋白质或可安装的修饰类型。在这里，我们报告了一种标记赖氨酸侧链ε-胺的策略，它将一种天然催化肽头尾环化的天冬酰胺连接酶重新用于与肽基质兼容的多功能异肽连接。我们发现，内部赖氨酸与相邻的亮氨酸残基可模拟传统的 N 端甘氨酸-亮氨酸底物。这种二肽结构可通过内部赖氨酸侧链实现高效的分子内或分子间连接，并通过等肽键将天冬酰胺 C 端与赖氨酸侧链连接在一起。通过化学酶法合成具有非原生 C 端到侧链拓扑结构的肽，以及将化学修饰的肽与重组蛋白连接，证明了这种方法的多功能性。
{"title":"Repurposing a plant peptide cyclase for targeted lysine acylation","authors":"Fabian B. H. Rehm, Tristan J. Tyler, Yan Zhou, Yen-Hua Huang, Conan K. Wang, Nicole Lawrence, David J. Craik, Thomas Durek","doi":"10.1038/s41557-024-01520-1","DOIUrl":"10.1038/s41557-024-01520-1","url":null,"abstract":"Transpeptidases are powerful tools for protein engineering but are largely restricted to acting at protein backbone termini. Alternative enzymatic approaches for internal protein labelling require bulky recognition motifs or non-proteinogenic reaction partners, potentially restricting which proteins can be modified or the types of modification that can be installed. Here we report a strategy for labelling lysine side chain ε-amines by repurposing an engineered asparaginyl ligase, which naturally catalyses peptide head-to-tail cyclization, for versatile isopeptide ligations that are compatible with peptidic substrates. We find that internal lysines with an adjacent leucine residue mimic the conventional N-terminal glycine–leucine substrate. This dipeptide motif enables efficient intra- or intermolecular ligation through internal lysine side chains, minimally leaving an asparagine C-terminally linked to the lysine side chain via an isopeptide bond. The versatility of this approach is demonstrated by the chemoenzymatic synthesis of peptides with non-native C terminus-to-side chain topology and the conjugation of chemically modified peptides to recombinant proteins. Plant asparaginyl endopeptidases that function preferentially as transpeptidases naturally catalyse the head-to-tail cyclization of plant peptides. Using substrate mimicry and reaction optimization, their function has now been repurposed to catalyse intermolecular isopeptide bond formation on diverse peptide and protein substrates.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":19.2,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41557-024-01520-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141091869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anaerobic ammonium oxidation (anammox)—the biological process that activates ammonium with nitrite—is responsible for a significant fraction of N2 production in marine environments. Despite decades of biochemical research, however, no synthetic models capable of anammox have been identified. Here we report that a copper sulfide mineral replicates the entire biological anammox pathway catalysed by three metalloenzymes. We identified a copper–nitrosonium {CuNO}10 complex, formed by nitrite reduction, as the oxidant for ammonium oxidation that leads to heterolytic N–N bond formation from nitrite and ammonium. Similar to the biological process, N2 production was mediated by the highly reactive intermediate hydrazine, one of the most potent reductants in nature. We also found another pathway involving N–N bond heterocoupling for the formation of hybrid N2O, a potent greenhouse gas with a unique isotope composition. Our study represents a rare example of non-enzymatic anammox reaction that interconnects six redox states in the abiotic nitrogen cycle.
{"title":"Copper sulfide mineral performs non-enzymatic anaerobic ammonium oxidation through a hydrazine intermediate","authors":"Daoping He, Kiyohiro Adachi, Daisuke Hashizume, Ryuhei Nakamura","doi":"10.1038/s41557-024-01537-6","DOIUrl":"https://doi.org/10.1038/s41557-024-01537-6","url":null,"abstract":"<p>Anaerobic ammonium oxidation (anammox)—the biological process that activates ammonium with nitrite—is responsible for a significant fraction of N<sub>2</sub> production in marine environments. Despite decades of biochemical research, however, no synthetic models capable of anammox have been identified. Here we report that a copper sulfide mineral replicates the entire biological anammox pathway catalysed by three metalloenzymes. We identified a copper–nitrosonium {CuNO}<sup>10</sup> complex, formed by nitrite reduction, as the oxidant for ammonium oxidation that leads to heterolytic N–N bond formation from nitrite and ammonium. Similar to the biological process, N<sub>2</sub> production was mediated by the highly reactive intermediate hydrazine, one of the most potent reductants in nature. We also found another pathway involving N–N bond heterocoupling for the formation of hybrid N<sub>2</sub>O, a potent greenhouse gas with a unique isotope composition. Our study represents a rare example of non-enzymatic anammox reaction that interconnects six redox states in the abiotic nitrogen cycle.</p><figure></figure>","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141091886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1038/s41557-024-01541-w
Sayad Doobary, Berit Olofsson
Although functionalized cyclopropenes have found uses in many applications, their synthesis has been severely limited. Now, a hypervalent iodine reagent, in conjunction with gold catalysis, has been utilized to control their reactivity, allowing efficient formation of cyclopropenyl alkynes/alkenes.
{"title":"Cyclopropenium functionalization","authors":"Sayad Doobary, Berit Olofsson","doi":"10.1038/s41557-024-01541-w","DOIUrl":"10.1038/s41557-024-01541-w","url":null,"abstract":"Although functionalized cyclopropenes have found uses in many applications, their synthesis has been severely limited. Now, a hypervalent iodine reagent, in conjunction with gold catalysis, has been utilized to control their reactivity, allowing efficient formation of cyclopropenyl alkynes/alkenes.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1038/s41557-024-01535-8
Xiangdong Li, Matthew D. Wodrich, Jérôme Waser
Cyclopropenes are the smallest unsaturated carbocycles. Removing one substituent from cyclopropenes leads to cyclopropenium cations (C3+ systems, CPCs). Stable aromatic π-type CPCs were discovered by Breslow in 1957 by removing a substituent on the aliphatic position. In contrast, σ-type CPCs—formally accessed by removing one substituent on the alkene—are unstable and relatively unexplored. Here we introduce electrophilic cyclopropenyl-gold(III) species as equivalents of σ-type CPCs, which can then react with terminal alkynes and vinylboronic acids. With catalyst loadings as low as 2 mol%, the synthesis of highly functionalized alkynyl- or alkenyl-cyclopropenes proceeded under mild conditions. A class of hypervalent iodine reagents—the cyclopropenyl benziodoxoles (CpBXs)—enabled the direct oxidation of gold(I) to gold(III) with concomitant transfer of a cyclopropenyl group. This protocol was general, tolerant to numerous functional groups and could be used for the late-stage modification of complex natural products, bioactive molecules and pharmaceuticals. The σ-type cyclopropenium cations (CPCs) are unstable species and currently underdeveloped. Now, an iodine(III)-based cyclopropenyl transfer reagent has been developed, which can generate electrophilic cyclopropenyl-gold(III) species as equivalents of σ-type CPCs. The synthetic potential has been demonstrated by the transfer of σ-type CPCs to terminal alkynes and vinylboronic acids.
{"title":"Accessing elusive σ-type cyclopropenium cation equivalents through redox gold catalysis","authors":"Xiangdong Li, Matthew D. Wodrich, Jérôme Waser","doi":"10.1038/s41557-024-01535-8","DOIUrl":"10.1038/s41557-024-01535-8","url":null,"abstract":"Cyclopropenes are the smallest unsaturated carbocycles. Removing one substituent from cyclopropenes leads to cyclopropenium cations (C3+ systems, CPCs). Stable aromatic π-type CPCs were discovered by Breslow in 1957 by removing a substituent on the aliphatic position. In contrast, σ-type CPCs—formally accessed by removing one substituent on the alkene—are unstable and relatively unexplored. Here we introduce electrophilic cyclopropenyl-gold(III) species as equivalents of σ-type CPCs, which can then react with terminal alkynes and vinylboronic acids. With catalyst loadings as low as 2 mol%, the synthesis of highly functionalized alkynyl- or alkenyl-cyclopropenes proceeded under mild conditions. A class of hypervalent iodine reagents—the cyclopropenyl benziodoxoles (CpBXs)—enabled the direct oxidation of gold(I) to gold(III) with concomitant transfer of a cyclopropenyl group. This protocol was general, tolerant to numerous functional groups and could be used for the late-stage modification of complex natural products, bioactive molecules and pharmaceuticals. The σ-type cyclopropenium cations (CPCs) are unstable species and currently underdeveloped. Now, an iodine(III)-based cyclopropenyl transfer reagent has been developed, which can generate electrophilic cyclopropenyl-gold(III) species as equivalents of σ-type CPCs. The synthetic potential has been demonstrated by the transfer of σ-type CPCs to terminal alkynes and vinylboronic acids.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41557-024-01535-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.1038/s41557-024-01539-4
Yu Wang, Cheng Bi, Yu Kawamata, Lauren N. Grant, Lacey Samp, Paul F. Richardson, Shasha Zhang, Kaid C. Harper, Maximilian D. Palkowitz, Aristidis Vasilopoulos, Michael R. Collins, Martins S. Oderinde, Chet C. Tyrol, Doris Chen, Erik A. LaChapelle, Jake B. Bailey, Jennifer X. Qiao, Phil S. Baran
Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N–X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up). Electrophilic halogenation approaches often suffer from low reactivity and chemoselectivity when it comes to complex compounds. Now a class of halogenating reagents based on anomeric amides that can halogenate complex bioactive molecules with diverse functional groups and heterocycles has been developed. The higher reactivity of these anomeric amide reagents is attributed to the energy stored in the pyramidalized nitrogen.
{"title":"Discovery of N–X anomeric amides as electrophilic halogenation reagents","authors":"Yu Wang, Cheng Bi, Yu Kawamata, Lauren N. Grant, Lacey Samp, Paul F. Richardson, Shasha Zhang, Kaid C. Harper, Maximilian D. Palkowitz, Aristidis Vasilopoulos, Michael R. Collins, Martins S. Oderinde, Chet C. Tyrol, Doris Chen, Erik A. LaChapelle, Jake B. Bailey, Jennifer X. Qiao, Phil S. Baran","doi":"10.1038/s41557-024-01539-4","DOIUrl":"10.1038/s41557-024-01539-4","url":null,"abstract":"Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N–X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up). Electrophilic halogenation approaches often suffer from low reactivity and chemoselectivity when it comes to complex compounds. Now a class of halogenating reagents based on anomeric amides that can halogenate complex bioactive molecules with diverse functional groups and heterocycles has been developed. The higher reactivity of these anomeric amide reagents is attributed to the energy stored in the pyramidalized nitrogen.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":19.2,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141069410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1038/s41557-024-01530-z
Ravi Yadav, Avijit Maiti, Marcel Schorpp, Jürgen Graf, Florian Weigend, Lutz Greb
Aromaticity in organic molecules is well defined, but its role in metal-only rings remains controversial. Here we introduce a supramolecular stabilization approach of a cationic {Bi4} rhomboid within the symmetric charge sphere of two bowl-shaped dianionic calix[4]pyrrolato indinates. Crystallographic and spectroscopic characterization, quantum chemical analysis and magnetically induced ring currents indicate σ-aromaticity in the formally tetracationic 16-valence electron [Bi4]4+ ring. Computational screening for other p-block elements identifies the planar rhomboid as the globally preferred structure for 16-valence electron four-atomic clusters. The aromatic [Bi4]4+ is isoelectronic to the [Al4]4−, a motif previously observed as antiaromatic in Li3[Al4]− in the gas phase. Thus, subtle factors such as charge isotropy seem to decide over aromaticity or antiaromaticity, advising for caution in debates based on the Hückel model—a concept valid for second-row elements but less deterministic for the heavier congeners. The synthesis of cationic all-metal aromatic systems without covalent functionalization remains an underexplored area in chemistry. Now a tetracationic [Bi4]4+ featuring all-metal σ-aromaticity has been stabilized through a supramolecular approach relying on dianionic calix[4]pyrrolato indiumbromide shells. This planar rhomboid represents the global minimum for 16 valence electron systems.
{"title":"Supramolecular trapping of a cationic all-metal σ-aromatic {Bi4} ring","authors":"Ravi Yadav, Avijit Maiti, Marcel Schorpp, Jürgen Graf, Florian Weigend, Lutz Greb","doi":"10.1038/s41557-024-01530-z","DOIUrl":"10.1038/s41557-024-01530-z","url":null,"abstract":"Aromaticity in organic molecules is well defined, but its role in metal-only rings remains controversial. Here we introduce a supramolecular stabilization approach of a cationic {Bi4} rhomboid within the symmetric charge sphere of two bowl-shaped dianionic calix[4]pyrrolato indinates. Crystallographic and spectroscopic characterization, quantum chemical analysis and magnetically induced ring currents indicate σ-aromaticity in the formally tetracationic 16-valence electron [Bi4]4+ ring. Computational screening for other p-block elements identifies the planar rhomboid as the globally preferred structure for 16-valence electron four-atomic clusters. The aromatic [Bi4]4+ is isoelectronic to the [Al4]4−, a motif previously observed as antiaromatic in Li3[Al4]− in the gas phase. Thus, subtle factors such as charge isotropy seem to decide over aromaticity or antiaromaticity, advising for caution in debates based on the Hückel model—a concept valid for second-row elements but less deterministic for the heavier congeners. The synthesis of cationic all-metal aromatic systems without covalent functionalization remains an underexplored area in chemistry. Now a tetracationic [Bi4]4+ featuring all-metal σ-aromaticity has been stabilized through a supramolecular approach relying on dianionic calix[4]pyrrolato indiumbromide shells. This planar rhomboid represents the global minimum for 16 valence electron systems.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":19.2,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41557-024-01530-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1038/s41557-024-01507-y
Toby Journeaux, Gonçalo J. L. Bernardes
Many systemic cancer chemotherapies comprise a combination of drugs, yet all clinically used antibody–drug conjugates (ADCs) contain a single-drug payload. These combination regimens improve treatment outcomes by producing synergistic anticancer effects and slowing the development of drug-resistant cell populations. In an attempt to replicate these regimens and improve the efficacy of targeted therapy, the field of ADCs has moved towards developing techniques that allow for multiple unique payloads to be attached to a single antibody molecule with high homogeneity. However, the methods for generating such constructs—homogeneous multi-payload ADCs—are both numerous and complex owing to the plethora of reactive functional groups that make up the surface of an antibody. Here, by summarizing and comparing the methods of both single- and multi-payload ADC generation and their key preclinical and clinical results, we provide a timely overview of this relatively new area of research. The methods discussed range from branched linker installation to the incorporation of unnatural amino acids, with a generalized comparison tool of the most promising modification strategies also provided. Finally, the successes and challenges of this rapidly growing field are critically evaluated, and from this, future areas of research and development are proposed. Multi-payload antibody–drug conjugates (ADCs) are an emerging class of targeted therapeutics. Comprising a monoclonal antibody with multiple unique payloads attached, these constructs have the potential to produce synergistic anticancer effects with reduced therapeutic resistance. In this Review, methods for generating multi-payload ADCs are discussed, highlighting some key preclinical results.
{"title":"Homogeneous multi-payload antibody–drug conjugates","authors":"Toby Journeaux, Gonçalo J. L. Bernardes","doi":"10.1038/s41557-024-01507-y","DOIUrl":"10.1038/s41557-024-01507-y","url":null,"abstract":"Many systemic cancer chemotherapies comprise a combination of drugs, yet all clinically used antibody–drug conjugates (ADCs) contain a single-drug payload. These combination regimens improve treatment outcomes by producing synergistic anticancer effects and slowing the development of drug-resistant cell populations. In an attempt to replicate these regimens and improve the efficacy of targeted therapy, the field of ADCs has moved towards developing techniques that allow for multiple unique payloads to be attached to a single antibody molecule with high homogeneity. However, the methods for generating such constructs—homogeneous multi-payload ADCs—are both numerous and complex owing to the plethora of reactive functional groups that make up the surface of an antibody. Here, by summarizing and comparing the methods of both single- and multi-payload ADC generation and their key preclinical and clinical results, we provide a timely overview of this relatively new area of research. The methods discussed range from branched linker installation to the incorporation of unnatural amino acids, with a generalized comparison tool of the most promising modification strategies also provided. Finally, the successes and challenges of this rapidly growing field are critically evaluated, and from this, future areas of research and development are proposed. Multi-payload antibody–drug conjugates (ADCs) are an emerging class of targeted therapeutics. Comprising a monoclonal antibody with multiple unique payloads attached, these constructs have the potential to produce synergistic anticancer effects with reduced therapeutic resistance. In this Review, methods for generating multi-payload ADCs are discussed, highlighting some key preclinical results.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":21.8,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1038/s41557-024-01534-9
Josef T. Boronski, Agamemnon E. Crumpton, Aisling F. Roper, Simon Aldridge
Owing to its high toxicity, the chemistry of element number four, beryllium, is poorly understood. However, as the lightest elements provide the basis for fundamental models of chemical bonding, there is a need for greater insight into the properties of beryllium. In this context, the chemistry of the homo-elemental Be–Be bond is of fundamental interest. Here the ligand metathesis chemistry of diberyllocene (1; CpBeBeCp)—a stable complex with a Be–Be bond—has been investigated. These studies yield two complexes with Be–Be bonds: Cp*BeBeCp (2) and [K{(HCDippN)2BO}2]BeBeCp (3; Dipp = 2,6-diisopropylphenyl). Quantum chemical calculations indicate that the Be–Be bond in 3 is polarized to such an extent that the complex could be formulated as a mixed-oxidation state Be0/BeII complex. Correspondingly, it is demonstrated that 3 can transfer the ‘beryllyl’ anion, [BeCp]−, to an organic substrate, by analogy with the reactivity of sp2–sp3 diboranes. Indeed, this work reveals striking similarities between the homo-elemental bonding linkages of beryllium and boron, despite the respective metallic and non-metallic natures of these elements. The chemistry of beryllium, one of the periodic table’s lightest elements, remains poorly understood. Now, a nucleophilic beryllium complex with a highly polarized Be–Be bond has been prepared—this compound could be seen as a mixed-oxidation state Be(0)/Be(II) complex. The Be–Be bond is cleaved upon reaction with an organic substrate.
{"title":"A nucleophilic beryllyl complex via metathesis at [Be–Be]2+","authors":"Josef T. Boronski, Agamemnon E. Crumpton, Aisling F. Roper, Simon Aldridge","doi":"10.1038/s41557-024-01534-9","DOIUrl":"10.1038/s41557-024-01534-9","url":null,"abstract":"Owing to its high toxicity, the chemistry of element number four, beryllium, is poorly understood. However, as the lightest elements provide the basis for fundamental models of chemical bonding, there is a need for greater insight into the properties of beryllium. In this context, the chemistry of the homo-elemental Be–Be bond is of fundamental interest. Here the ligand metathesis chemistry of diberyllocene (1; CpBeBeCp)—a stable complex with a Be–Be bond—has been investigated. These studies yield two complexes with Be–Be bonds: Cp*BeBeCp (2) and [K{(HCDippN)2BO}2]BeBeCp (3; Dipp = 2,6-diisopropylphenyl). Quantum chemical calculations indicate that the Be–Be bond in 3 is polarized to such an extent that the complex could be formulated as a mixed-oxidation state Be0/BeII complex. Correspondingly, it is demonstrated that 3 can transfer the ‘beryllyl’ anion, [BeCp]−, to an organic substrate, by analogy with the reactivity of sp2–sp3 diboranes. Indeed, this work reveals striking similarities between the homo-elemental bonding linkages of beryllium and boron, despite the respective metallic and non-metallic natures of these elements. The chemistry of beryllium, one of the periodic table’s lightest elements, remains poorly understood. Now, a nucleophilic beryllium complex with a highly polarized Be–Be bond has been prepared—this compound could be seen as a mixed-oxidation state Be(0)/Be(II) complex. The Be–Be bond is cleaved upon reaction with an organic substrate.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":19.2,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41557-024-01534-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1038/s41557-024-01525-w
Michael Phillips, Kingshuk Ghosh
Liquid droplets form in cells to concentrate specific biomolecules (while excluding others) in order to perform specific functions. The molecular mechanisms that determine whether different macromolecules undergo co-partitioning or exclusion has so far remained elusive. Now, two studies uncover key principles underlying this selectivity.
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