Theranostics Molecular Beacons of Xeno-Nucleic Acid for Detecting
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Peptide Nucleic Acids, Morpholinos and Related Antisense Biomolecules
MEDICAL INTELLIGENCE UNIT Peptide Nucleic Acids, Morpholinos and Related Antisense Biomolecules Christopher G. Janson, M.D. Departments of Neurosurgery, Neurology and Molecular Genetics Cell and Gene Therapy Center UMDNJ-Robert Wood Johnson Medical School Camden, New Jersey, U.S.A. Matthew J. During, M.D., ScD. Department of Molecular Medicine and Pathology University of Auckland Auckland, New Zealand LANDES BIOSCIENCE / EUREKAH.COM KLUWER ACADEMIC / PLENUM PUBLISHERS GEORGETOWN, TEXAS NEW YORK, NEW YORK USA U.SA PEPTIDE NUCLEIC ACIDS, MORPHOLINOS AND RELATED ANTISENSE BIOMOLECULES Medical Intelligence Unit Landes Bioscience / Eurekah.com Kluwer Academic / Plenum Publishers Copyright ©2006 Eurekah.com and Kluwer Academic / Plenum Publishers All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher, vdth the exception of any material supplied specifically for the purpose of being entered and executed on a computer system; for exclusive use by the Purchaser of the work. Printed in the U.S.A. Kluwer Academic / Plenum PubHshers, 233 Spring Street, New York, New York, U.S.A. 10013 http ://www.wkap .nl/ Please address all inquiries to the Publishers: Landes Bioscience / Eurekah.com, 810 South Church Street, Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 http ://v^^ww.eurekah. com http://www.landesbioscience.com Peptide -
(12) Patent Application Publication (10) Pub. No.: US 2013/0203610 A1 Meller Et Al
US 20130203610A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0203610 A1 Meller et al. (43) Pub. Date: Aug. 8, 2013 (54) TOOLS AND METHOD FOR NANOPORES Related U.S. Application Data UNZIPPING-DEPENDENT NUCLECACID (60) Provisional application No. 61/318,872, filed on Mar. SEQUENCING 30, 2010. (75) Inventors: Amit Meller, Brookline, MA (US); Alon Publication Classification Singer, Brighton, MA (US) (51) Int. Cl. (73) Assignee: TRUSTEES OF BOSTON CI2O I/68 (2006.01) UNIVERSITY, Boston, MA (US) (52) U.S. Cl. CPC .................................... CI2O I/6874 (2013.01) (21) Appl. No.: 13/638,455 USPC ................................................. 506/6:506/16 (57) ABSTRACT (22) PCT Filed: Mar. 30, 2011 Provided herein is a library that comprises a plurality of molecular beacons (MBs), each MB having a detectable (86). PCT No.: PCT/US2O11AO3O430 label, a detectable label blocker and a modifier group. The S371 (c)(1), library is used in conjunction with nanopore unzipping-de (2), (4) Date: Apr. 17, 2013 pendent sequencing of nucleic acids. Patent Application Publication Aug. 8, 2013 Sheet 1 of 18 US 2013/020361.0 A1 . N s Patent Application Publication Aug. 8, 2013 Sheet 2 of 18 US 2013/020361.0 A1 I’9IAI ::::::::::: Dº3.modoueN Patent Application Publication Aug. 8, 2013 Sheet 3 of 18 US 2013/020361.0 A1 Z’9IAI ~~~~~~~~~);........ Patent Application Publication Aug. 8, 2013 Sheet 4 of 18 US 2013/020361.0 A1 s :·.{-zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz iii. 9 iii.338 lii &S Patent Application Publication Aug. 8, 2013 Sheet 5 of 18 US 2013/020361.0 A1 s r Patent Application Publication Aug. -
Alternative Biochemistries for Alien Life: Basic Concepts and Requirements for the Design of a Robust Biocontainment System in Genetic Isolation
G C A T T A C G G C A T genes Review Alternative Biochemistries for Alien Life: Basic Concepts and Requirements for the Design of a Robust Biocontainment System in Genetic Isolation Christian Diwo 1 and Nediljko Budisa 1,2,* 1 Institut für Chemie, Technische Universität Berlin Müller-Breslau-Straße 10, 10623 Berlin, Germany; [email protected] 2 Department of Chemistry, University of Manitoba, 144 Dysart Rd, 360 Parker Building, Winnipeg, MB R3T 2N2, Canada * Correspondence: [email protected] or [email protected]; Tel.: +49-30-314-28821 or +1-204-474-9178 Received: 27 November 2018; Accepted: 21 December 2018; Published: 28 December 2018 Abstract: The universal genetic code, which is the foundation of cellular organization for almost all organisms, has fostered the exchange of genetic information from very different paths of evolution. The result of this communication network of potentially beneficial traits can be observed as modern biodiversity. Today, the genetic modification techniques of synthetic biology allow for the design of specialized organisms and their employment as tools, creating an artificial biodiversity based on the same universal genetic code. As there is no natural barrier towards the proliferation of genetic information which confers an advantage for a certain species, the naturally evolved genetic pool could be irreversibly altered if modified genetic information is exchanged. We argue that an alien genetic code which is incompatible with nature is likely to assure the inhibition of all mechanisms of genetic information transfer in an open environment. The two conceivable routes to synthetic life are either de novo cellular design or the successive alienation of a complex biological organism through laboratory evolution. -
New Constrained Amino Acids and Peptide Nucleic Acid Building Blocks for the Construction of Bio-Polymers Alexandra Gresika
New constrained amino acids and peptide nucleic acid building blocks for the construction of bio-polymers Alexandra Gresika To cite this version: Alexandra Gresika. New constrained amino acids and peptide nucleic acid building blocks for the construction of bio-polymers. Other. Université Côte d’Azur, 2018. English. NNT : 2018AZUR4104. tel-02073232 HAL Id: tel-02073232 https://tel.archives-ouvertes.fr/tel-02073232 Submitted on 19 Mar 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE DE DOCTORAT Nouveaux synthons contraints de type - amino acides et PNA en vue de l´élaboration de bio-foldamères New constrained amino acids and peptide nucleic acid building blocks for the construction of biopolymers Alexandra Gresika Molécules Bioactives Présentée en vue de l’obtention Devant le jury, composé de : du grade de docteur en Chimie Muriel Amblard, Directrice de Recherche d’Université Côte d’Azur CNRS, IBMM UMR 5247, Université de Dirigée par : Nadia Patino Montpellier Karine Alvarez, Chargée de Recherche Soutenue le : 16.11.2018 CNRS, AFBM UMR 7257, Université Aix- Marseille Mohamed Mehiri, Maître de Conférences, ICN UMR 7272, Université Côte d’Azur Nadia Patino, Professeur des Universités, ICN UMR 7272, Université Côte d’Azur 1 New constrained amino acids and peptide nucleic acid building blocks for the construction of bio-polymers. -
Threose Nucleic Acid
2/23/11! Something else…! •" Neither the chicken nor the egg came first! Alternative Ideas! •" Transitional forms that were later discarded! Or was it the “egkin”?! Some experiments with peptide nucleic acid! Threose Nucleic Acid (TNA)! (PNA).! PNA: Peptide backbone with bases! •" Threose is one of two sugars with a four- sided ring! Can act as template for polymerization of RNA! •" Fewer issues with incorrect linkages, From activated nucleotides! selection of correct handedness! (Böhler, et al., Nature, 376, 578! •" Replace ribose sugar in RNA with threose! & comments by Piccirilli, pg. 548 17 Aug. 1995! •" Can base pair with RNA! •" Could have preceded RNA! PNA could be simpler to form under prebiotic conditions! Main point is that a simpler thing (not necessarily PNA) ! could have preceded RNA! 1! 2/23/11! Focus on Energy! Membranes! G. Wächtershäuser! Inorganic - organic connection! •" Membranes provide enclosure! FeS2 ! (Iron pyrite)! –"Also fundamental for metabolism! Attracts negatively charged molecules ! •" Membranes never arise from scratch! Surface catalysis provides energy via formation from! –"Always passed down and added to! FeS + H2S! –"All derived from ancestral cell! •" T. Cavalier-Smith proposes membranes! Scene is hot sulfur vents on sea floor! –"Plus nucleic acid formed “ob-cell”! Some successes in simulations! Amino acids formed peptide bonds! –"Merger of 2 ob-cells formed first cell! Thioester World! H O 1." Need precursor to RNA world! H H S H O Thioester! S C. de Duve! C C O 2. !Need energy conversion! In Vital Dust! O !Protometabolism! Thiol + Carboxyl! Background:! H O H H O H O Ester! O Thiols involved in metabolism, particularly in ancient ! C C pathways! O O Hydroxyl + Carboxyl! Also can catalyze ester formation by group transfer! Reactions! e.g. -
Advances in Oligonucleotide Drug Delivery
REVIEWS Advances in oligonucleotide drug delivery Thomas C. Roberts 1,2 ✉ , Robert Langer 3 and Matthew J. A. Wood 1,2 ✉ Abstract | Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches — including chemical modification, bioconjugation and the use of nanocarriers — which aim to address the delivery challenge. Oligonucleotides are nucleic acid polymers with the In addition to their ability to recognize specific tar- potential to treat or manage a wide range of diseases. get sequences via complementary base pairing, nucleic Although the majority of oligonucleotide therapeutics acids can also interact with proteins through the for- have focused on gene silencing, other strategies are being mation of three-dimensional secondary structures — a pursued, including splice modulation and gene activa- property that is also being exploited therapeutically. For tion, expanding the range of possible targets beyond example, nucleic acid aptamers are structured -
Guide for Morpholino Users: Toward Therapeutics
Open Access Journal of Drug Discovery, Development and Delivery Special Article - Antisense Drug Research and Development Guide for Morpholino Users: Toward Therapeutics Moulton JD* Gene Tools, LLC, USA Abstract *Corresponding author: Moulton JD, Gene Tools, Morpholino oligos are uncharged molecules for blocking sites on RNA. They LLC, 1001 Summerton Way, Philomath, Oregon 97370, are specific, soluble, non-toxic, stable, and effective antisense reagents suitable USA for development as therapeutics and currently in clinical trials. They are very versatile, targeting a wide range of RNA targets for outcomes such as blocking Received: January 28, 2016; Accepted: April 29, 2016; translation, modifying splicing of pre-mRNA, inhibiting miRNA maturation and Published: May 03, 2016 activity, as well as less common biological targets and diagnostic applications. Solutions have been developed for delivery into a range of cultured cells, embryos and adult animals; with development of a non-toxic and effective system for systemic delivery, Morpholinos have potential for broad therapeutic development targeting pathogens and genetic disorders. Keywords: Splicing; Duchenne muscular dystrophy; Phosphorodiamidate morpholino oligos; Internal ribosome entry site; Nonsense-mediated decay Morpholinos: Research Applications, the transcript from miRNA regulation; Therapeutic Promise • Block regulatory proteins from binding to RNA, shifting Morpholino oligos bind to complementary sequences of RNA alternative splicing; and get in the way of processes. Morpholino oligos are commonly • Block association of RNAs with cytoskeletal motor protein used to prevent a particular protein from being made in an organism complexes, preventing RNA translocation; or cell culture. Morpholinos are not the only tool used for this: a protein’s synthesis can be inhibited by altering DNA to make a null • Inhibit poly-A tailing of pre-mRNA; mutant (called a gene knockout) or by interrupting processes on RNA • Trigger frame shifts at slippery sequences; (called a gene knockdown). -
De Novo Nucleic Acids: a Review of Synthetic Alternatives to DNA and RNA That Could Act As † Bio-Information Storage Molecules
life Review De Novo Nucleic Acids: A Review of Synthetic Alternatives to DNA and RNA That Could Act as y Bio-Information Storage Molecules Kevin G Devine 1 and Sohan Jheeta 2,* 1 School of Human Sciences, London Metropolitan University, 166-220 Holloway Rd, London N7 8BD, UK; [email protected] 2 Network of Researchers on the Chemical Evolution of Life (NoR CEL), Leeds LS7 3RB, UK * Correspondence: [email protected] This paper is dedicated to Professor Colin B Reese, Daniell Professor of Chemistry, Kings College London, y on the occasion of his 90th Birthday. Received: 17 November 2020; Accepted: 9 December 2020; Published: 11 December 2020 Abstract: Modern terran life uses several essential biopolymers like nucleic acids, proteins and polysaccharides. The nucleic acids, DNA and RNA are arguably life’s most important, acting as the stores and translators of genetic information contained in their base sequences, which ultimately manifest themselves in the amino acid sequences of proteins. But just what is it about their structures; an aromatic heterocyclic base appended to a (five-atom ring) sugar-phosphate backbone that enables them to carry out these functions with such high fidelity? In the past three decades, leading chemists have created in their laboratories synthetic analogues of nucleic acids which differ from their natural counterparts in three key areas as follows: (a) replacement of the phosphate moiety with an uncharged analogue, (b) replacement of the pentose sugars ribose and deoxyribose with alternative acyclic, pentose and hexose derivatives and, finally, (c) replacement of the two heterocyclic base pairs adenine/thymine and guanine/cytosine with non-standard analogues that obey the Watson–Crick pairing rules. -
Darwinian Evolution of an Alternative Genetic System Provides Support for TNA As an RNA Progenitor Hanyang Yu†,Suzhang† and John C
ARTICLES PUBLISHED ONLINE: 10 JANUARY 2012 | DOI: 10.1038/NCHEM.1241 Darwinian evolution of an alternative genetic system provides support for TNA as an RNA progenitor Hanyang Yu†,SuZhang† and John C. Chaput* The pre-RNA world hypothesis postulates that RNA was preceded in the evolution of life by a simpler genetic material, but it is not known if such systems can fold into structures capable of eliciting a desired function. Presumably, whatever chemistry gave rise to RNA would have produced other RNA analogues, some of which may have preceded or competed directly with RNA. Threose nucleic acid (TNA), a potentially natural derivative of RNA, has received considerable interest as a possible RNA progenitor due to its chemical simplicity and ability to exchange genetic information with itself and RNA. Here, we have applied Darwinian evolution methods to evolve, in vitro, a TNA receptor that binds to an arbitrary target with high affinity and specificity. This demonstration shows that TNA has the ability to fold into tertiary structures with sophisticated chemical functions, which provides evidence that TNA could have served as an ancestral genetic system during an early stage of life. he question of why nature chose ribofuranosyl nucleic acids as like DNA and RNA, can fold into structures with complicated func- the molecular basis of life’s genetic material has prompted a tions—a prerequisite for any RNA progenitor in a hypothetical Tsystematic analysis of nucleic acid structure with regard to pre-RNA world. the chemical etiology of RNA1. Results from these studies reveal that several potentially natural RNA alternatives are capable of Results and discussion Watson–Crick base pairing, demonstrating the capacity for these The discovery by Eschenmoser and colleagues that TNA can molecules to store genetic information. -
Conformation and Polymorphism in PNA-DNA and PNA-RNA Hybrids (Chimera/Duplex/Triple Helix/Molecular Mechanics)
Proc. Natl. Acad. Sci. USA Vol. 90, pp. 9542-9546, October 1993 Biochemistry Peptide nucleic acid (PNA) conformation and polymorphism in PNA-DNA and PNA-RNA hybrids (chimera/duplex/triple helix/molecular mechanics) ORN ALMARSSON AND THOMAS C. BRUICE Department of Chemistry, University of California at Santa Barbara, Santa Barbara, CA 93106 Contributed by Thomas C. Bruice, July 19, 1993 ABSTRACT Two hydrogen-bonding motifs have been pro- nucleic acids, is their stability toward nucleases. Although the posed to account for the extraordinary stability of polyamide designing of the PNA analogues of DNA has been described "peptide" nucleic acid (PNA) hybrids with nucleic acids. These by the inventors (4), the design rationale does not explain the interresidue- and intraresidue-hydrogen-bond motifs were in- great stability of the PNA hybrids with nucleic acids, as vestigated by molecular mechanics calculations. Energy- exemplified by PNA-strand invasion of double-helical DNA. iinimized structures of Watson-Crick base-paired decameric Our recent molecular mechanics study (5) with the B-helix duplexes of PNA with A-, B-, and Z-DNA and A-RNA poly- structure of the DNA*PNA duplex (dAp)lo'(pnaT)lo [where morphs indicate that the inherent stability of the complemen- (dAp)10 is the decanucleotide of 2'-deoxyadenosine 5'- tary PNA helical structures is derived from interresidue, rather phosphate and (pnaT)lo is the decamer of thyminyl PNA with than from intraresidue, hydrogen bonds in all hybrids studied. lysine amide attached to the C terminus] strongly suggests that Intraresidue-hydrogen-bond lengths are consistently longer the stability of DNA*PNA duplexes is due to interresidue than interresidue hydrogen bonds. -
Dna Enzymes for Peptide-Nucleic Acid Conjugation and for Lysine Methylation
DNA ENZYMES FOR PEPTIDE-NUCLEIC ACID CONJUGATION AND FOR LYSINE METHYLATION BY CHIH-CHI CHU DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2017 Urbana, Illinois Doctoral Committee: Professor Scott K. Silverman, Chair Professor Paul J. Hergenrother Associate Professor Douglas A. Mitchell Professor Steven C. Zimmerman Abstract Proteins and RNA are known to be enzymes in nature. These biopolymers have complex secondary and tertiary structures that can enable substrate binding and catalysis. DNA is primarily double-stranded and is not known to be catalytic in nature. However, given the similarities in chemical structure between DNA and RNA, it is reasonable to think that single- stranded DNA can also form complex structures. In fact, artificial DNA enzymes have been identified in laboratories by in vitro selection. The identification of new enzymes favors the use of nucleic acids over proteins for several reasons. First, nucleic acids can be amplified by natural enzymes whereas proteins cannot be amplified in any way. Second, the number of possible sequences is smaller for nucleic acids (4n, where n is the length of the biopolymer) than for proteins (20n). Therefore, selection experiments for identifying nucleic acid enzymes will cover a larger fraction of total sequence space. Furthermore, of the sequence space that is covered, a large portion of nucleic acid sequences can fold into secondary or tertiary structures, whereas most random sequences of proteins often will not fold and thus will aggregate. Between the two nucleic acid polymers, DNA offers additional advantages over RNA because DNA can be directly amplified by polymerases whereas RNA requires an extra reverse transcription step. -
Design, Synthesis, and Characterization of Functional Click Nucleic
DESIGN, SYNTHESIS, AND CHARACTERIZATION OF FUNCTIONAL CLICK NUCLEIC ACID POLYMERS AND CONJUGATES FOR BIOLOGICAL APPLICATIONS By ALEX J. ANDERSON B.S., Vanderbilt University, 2015 M.S., University of Colorado, 2017 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemical and Biological Engineering 2020 Thesis committee: Dr. Christopher N. Bowman, Chair Dr. Stephanie J. Bryant Dr. Virginia L. Ferguson Dr. Jennifer N. Cha Dr. Frank Vernerey Abstract Anderson, Alex J. (PhD. Chemical and Biological Engineering) Design, Synthesis, and Characterization of Functional Click Nucleic Acid Polymers and Conjugates for Biological Applications Thesis directed by Christopher N. Bowman and Stephanie J. Bryant Oligonucleotides are a powerful class of biopolymer which, through Watson-and-Crick hydrogen bonding, are capable of directing the self-assembly of materials as well as recognizing and binding to very specific targets. These features have made oligonucleotides an attractive tool for uses in materials science and biotechnology. However, there are several drawbacks to the implementation of oligonucleotides with a natural backbone (i.e. DNA or RNA) including susceptibility to degradation and a limited scale of production. Click Nucleic Acids (CNAs) represent a new class of oligonucleotide that was designed to alleviate these issues. The distinguishing feature of CNAs is that they are polymerized via radical mediated thiol-ene click chemistry, which vastly increases the speed and scale of oligonucleotide synthesis. This thesis focuses on developing CNA polymers and conjugates and demonstrating the utility of CNAs as an alternative oligonucleotide for various biological applications.