Publications by authors named "Antony Crisp"

9 Publications

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A Click Chemistry Approach to Developing Molecularly Targeted DNA Scissors.

Chemistry 2020 Dec 5;26(70):16782-16792. Epub 2020 Nov 5.

School of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, 9, Ireland.

Nucleic acid click chemistry was used to prepare a family of chemically modified triplex forming oligonucleotides (TFOs) for application as a new gene-targeted technology. Azide-bearing phenanthrene ligands-designed to promote triplex stability and copper binding-were 'clicked' to alkyne-modified parallel TFOs. Using this approach, a library of TFO hybrids was prepared and shown to effectively target purine-rich genetic elements in vitro. Several of the hybrids provide significant stabilisation toward melting in parallel triplexes (>20 °C) and DNA damage can be triggered upon copper binding in the presence of added reductant. Therefore, the TFO and 'clicked' ligands work synergistically to provide sequence-selectivity to the copper cutting unit which, in turn, confers high stabilisation to the DNA triplex. To extend the boundaries of this hybrid system further, a click chemistry-based di-copper binding ligand was developed to accommodate designer ancillary ligands such as DPQ and DPPZ. When this ligand was inserted into a TFO, a dramatic improvement in targeted oxidative cleavage is afforded.
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http://dx.doi.org/10.1002/chem.202002860DOI Listing
December 2020

Amino Acid Modified RNA Bases as Building Blocks of an Early Earth RNA-Peptide World.

Chemistry 2020 Nov 14;26(65):14856-14860. Epub 2020 Oct 14.

Department of Chemistry, LMU München, Butenandtstr. 5-13, 81377, München, Germany.

Fossils of extinct species allow us to reconstruct the process of Darwinian evolution that led to the species diversity we see on Earth today. The origin of the first functional molecules able to undergo molecular evolution and thus eventually able to create life, are largely unknown. The most prominent idea in the field posits that biology was preceded by an era of molecular evolution, in which RNA molecules encoded information and catalysed their own replication. This RNA world concept stands against other hypotheses, that argue for example that life may have begun with catalytic peptides and primitive metabolic cycles. The question whether RNA or peptides were first is addressed by the RNA-peptide world concept, which postulates a parallel existence of both molecular species. A plausible experimental model of how such an RNA-peptide world may have looked like, however, is absent. Here we report the synthesis and physicochemical evaluation of amino acid containing adenosine bases, which are closely related to molecules that are found today in the anticodon stem-loop of tRNAs from all three kingdoms of life. We show that these adenosines lose their base pairing properties, which allow them to equip RNA with amino acids independent of the sequence context. As such we may consider them to be living molecular fossils of an extinct molecular RNA-peptide world.
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http://dx.doi.org/10.1002/chem.202002929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756884PMC
November 2020

Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides.

Science 2019 10;366(6461):76-82

Center for Integrated Protein Science, Department of Chemistry, LMU München, Butenandtstrasse 5-13, 81377 München, Germany.

Theories about the origin of life require chemical pathways that allow formation of life's key building blocks under prebiotically plausible conditions. Complex molecules like RNA must have originated from small molecules whose reactivity was guided by physico-chemical processes. RNA is constructed from purine and pyrimidine nucleosides, both of which are required for accurate information transfer, and thus Darwinian evolution. Separate pathways to purines and pyrimidines have been reported, but their concurrent syntheses remain a challenge. We report the synthesis of the pyrimidine nucleosides from small molecules and ribose, driven solely by wet-dry cycles. In the presence of phosphate-containing minerals, 5'-mono- and diphosphates also form selectively in one-pot reactions. The pathway is compatible with purine synthesis, allowing the concurrent formation of all Watson-Crick bases.
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http://dx.doi.org/10.1126/science.aax2747DOI Listing
October 2019

Proto-Urea-RNA (Wöhler RNA) Containing Unusually Stable Urea Nucleosides.

Angew Chem Int Ed Engl 2019 12 30;58(51):18691-18696. Epub 2019 Oct 30.

Center for Integrated Protein Science (CiPSM) at the Department of Chemistry, LMU München, Butenandtstr. 5-13, 81377, München, Germany.

The RNA world hypothesis assumes that life on Earth began with nucleotides that formed information-carrying RNA oligomers able to self-replicate. Prebiotic reactions leading to the contemporary nucleosides are now known, but their execution often requires specific starting materials and lengthy reaction sequences. It was therefore proposed that the RNA world was likely proceeded by a proto-RNA world constructed from molecules that were likely present on the early Earth in greater abundance. Herein, we show that the prebiotic starting molecules bis-urea (biuret) and tris-urea (triuret) are able to directly react with ribose. The urea-ribosides are remarkably stable because they are held together by a network of intramolecular, bifurcated hydrogen bonds. This even allowed the synthesis of phosphoramidite building blocks and incorporation of the units into RNA. Investigations of the nucleotides' base-pairing potential showed that triuret:G RNA base pairs closely resemble U:G wobble base pairs. Based on the probable abundance of urea on the early Earth, we postulate that urea-containing RNA bases are good candidates for a proto-RNA world.
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http://dx.doi.org/10.1002/anie.201911746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916321PMC
December 2019

Publisher Correction: Non-canonical nucleosides and chemistry of the emergence of life.

Nat Commun 2019 01 15;10(1):325. Epub 2019 Jan 15.

Department of Chemistry at the Ludwig-Maximilians Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.

The original version of this Article contained errors in the citations in the second, third and fourth sentences of the first paragraph of the 'Life and LUCA' section, which incorrectly read 'Its development is explained by Darwinian evolution, which must have begun with rudimentary "living" vesicles that at some point transitioned into what we call the last universal common ancestor (LUCA). LUCA is a hypothetical life form obtained from phylogenetic analysis from which all three kingdoms of life originated. To our understanding, LUCA already possessed the capacity to synthesize specific building blocks such as amino acids, nucleotides and lipids.' The correct version states '(LUCA)' in place of '(LUCA)', 'originated' instead of 'originated' and 'lipids' rather than 'lipids'. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-08340-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333768PMC
January 2019

Non-canonical nucleosides and chemistry of the emergence of life.

Nat Commun 2018 12 12;9(1):5174. Epub 2018 Dec 12.

Department of Chemistry at the Ludwig-Maximilians Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.

Prebiotic chemistry, driven by changing environmental parameters provides canonical and a multitude of non-canonical nucleosides. This suggests that Watson-Crick base pairs were selected from a diverse pool of nucleosides in a pre-Darwinian chemical evolution process.
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http://dx.doi.org/10.1038/s41467-018-07222-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289997PMC
December 2018

Rethinking the tools of the RNA world.

Elife 2018 06 15;7. Epub 2018 Jun 15.

Center for Integrated Protein Science, Ludwig-Maximilians-Universität München, Munich, Germany.

An artificially evolved ribozyme can catalyse the synthesis of RNA by using trinucleotide triphosphates as building blocks.
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http://dx.doi.org/10.7554/eLife.38297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003769PMC
June 2018

Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth-Generation by Prebiotic Methylations and Carbamoylations.

Angew Chem Int Ed Engl 2018 05 17;57(20):5943-5946. Epub 2018 Apr 17.

Center for Integrated Protein Science (CiPSM) at the Department, of Chemistry, LMU München, Butenandtstrasse 5-13, 81377, München, Germany.

The RNA-world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth.
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http://dx.doi.org/10.1002/anie.201801919DOI Listing
May 2018

Wet-dry cycles enable the parallel origin of canonical and non-canonical nucleosides by continuous synthesis.

Nat Commun 2018 01 11;9(1):163. Epub 2018 Jan 11.

Center for Integrated Protein Science Munich CiPSM at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377, Munich, Germany.

The molecules of life were created by a continuous physicochemical process on an early Earth. In this hadean environment, chemical transformations were driven by fluctuations of the naturally given physical parameters established for example by wet-dry cycles. These conditions might have allowed for the formation of (self)-replicating RNA as the fundamental biopolymer during chemical evolution. The question of how a complex multistep chemical synthesis of RNA building blocks was possible in such an environment remains unanswered. Here we report that geothermal fields could provide the right setup for establishing wet-dry cycles that allow for the synthesis of RNA nucleosides by continuous synthesis. Our model provides both the canonical and many ubiquitous non-canonical purine nucleosides in parallel by simple changes of physical parameters such as temperature, pH and concentration. The data show that modified nucleosides were potentially formed as competitor molecules. They could in this sense be considered as molecular fossils.
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http://dx.doi.org/10.1038/s41467-017-02639-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765019PMC
January 2018