Agilent Technologies, Inc.

University of Colorado

University Patents, Inc.

Competitive Technologies, Inc.

Other

Competitve Technologies, Inc.

Marvin H Caruthers

Douglas J Dellinger

Geraldine F Dellinger

Agnieszka Sierzchala

Zoltan Timar

Joel Myerson

John Nielsen

Jason R Betley

Zoltan Kupihar

Mark D Matteucci

Serge L Beaucage

Sibasish Paul

Stephen A Scaringe

Fernando Ferreira

Jeffrey William Jacobs

Michel G M Perbost

Wolfgang K-d Brill

Eric K Yau

Michael Ma

William S Marshall

Mithun Roy

Luca Monfregola

John Turner

Yitzhak Stabinsky

Bill J Peck

Michael Leineweber

Michael G M Perbost

Agnieska Sierzchala

Yun-Xi Ma

Darla A Graff

Subhadeep Roy

Douglas J Dollinger

Ayman Alawneh

Eric LeProust

Rakesh N Veedu

Peter Cogan

Moshe Leitner

Katarzyna Jastrzebska

Heera Krishna

Brian Stell

Geraldino Dellinger

Agnieszka B Sierzchala

Mithum Roy

Amine substituted morpholino oligonucleotides, other than the classical N,N-dimethylamino PMO analogue, and methods of efficiently synthesizing these oligonucleotides with high yield are provided. Morpholino oligonucleotides having thiophosphoramidate, phosphoramidate, and alkyl phosphoramidate linkers. Chimeras containing unmodified DNA/RNA and other analogs of DNA/RNA can be prepared. These oligonucleotides form duplexes with complementary DNA or RNA that are more stable than natural DNA or DNA/RNA complexes, are active with RNAse H1, and may be transfected into cells using standard lipid reagents. These analogues are therefore useful for numerous applications.

Synthesis of backbone modified morpholino oligonucleotides and chimeras using phosphoramidite chemistry

Oligonucleotides comprising phosphoramidimidate internucleotide linkages, and methods of efficiently synthesizing these oligonucleotides with high yield are provided. These oligonucleotides form duplexes with complementary DNA or RNA that are more stable than natural DNA or DNA/RNA complexes, are active with RNAse H1, and may be transfected into cells using standard lipid reagents. These analogues are therefore useful for numerous therapeutic antisense applications.

Synthesis and biological activity of phosphoramidimidate and phosphoramidate DNA

Aspects of the present disclosure include compositions that make use of phosphorus and/or nucleobase protecting groups which find use in the synthesis of long polynucleotides. Phosphorus protecting groups are provided that help increase the stepwise coupling yield and/or phosphorous protecting groups that can be removed during the oxidation step. Amidine nucleobase protecting groups are provided that find use in the subject compositions and methods which provides for e.g., increased resistance to depurination during polynucleotide synthesis. In some instances, the methods and compositions disclosed herein utilize a combination of the phosphorus and amidine nucleobase protecting groups in the synthesis of polynucleotides having a sequence of 200 or more monomeric units in length. Also provided are methods for synthesizing a polynucleotide (e.g., a DNA) using one or more compounds disclosed herein.

Phosphorous protecting groups and methods of preparation and use thereof

Improved compositions and methods for treating a disease or disorder through target exon skipping, and preferably muscular dystrophy by administering antisense thiomorpholino molecules capable of binding to a selected target site in the human dystrophin gene to induce exon skipping to produce a functional Dystrophin protein.

Thiomorpholino oligonucleotides for the treatment of muscular dystrophy

The present invention provides nucleosides an exocyclic amine-protected nucleoside of the formula: A-B where A is a 5'-protected ribose, 5&#x2032;-protected-2-deoxyribose, 5&#x2032;-protected-3&#x2032;-phosphoramidite ribose, or 5&#x2032;-protected-3&#x2032;-phosphoramidite-2-deoxyribose moiety; and B is a nucleobase having an exocyclic amine group that is protected with di-tert-butylisobutylsilyl ('BIBS') protecting group. Use of BIBS protecting group provides an exocyclic amine-protected nucleoside that is stable to a wide variety of reaction conditions associated with oligonucleotide synthesis. The present invention also provides, oligonucleotides comprising the same, and methods for producing the same.

Exocyclic nitrogen atom protected nucleoside and method for producing and using the same

Aspects of the invention include 2' protected nucleoside monomers that are protected at the 2&#x2032; site with thiocarbon protecting groups. Thiocarbon protecting groups of interest include thiocarbonate, thionocarbonate, dithiocarbonate groups, as well as thionocarbamate protecting groups. Aspects of the invention further include nucleic acids that include the protecting groups of the invention, as well as methods of synthesizing nucleic acids using the protecting groups of the invention.

Thiocarbon-protecting groups for RNA synthesis

Methods of deprotecting polynucleotides are disclosed. One aspect of the method of deprotecting polynucleotides, among others, includes: providing a polynucleotide, wherein the polynucleotide includes at least one nucleotide monomer that has at least one protecting group selected from the following: a base having a protecting group, a 2'-hydroxyl protecting group, and a combination thereof, and deprotecting at least one of the protecting groups of the polynucleotide by introducing the polynucleotide to a solution including an &#x3b1;-effect nucleophile.

Solutions, methods, and processes for deprotection of polynucleotides

The invention provides methods for synthesizing oligonucleotides using nucleoside monomers having carbonate protected hydroxyl groups that are deprotected with &#x3b1;-effect nucleophiles. The &#x3b1;-effect nucleophile irreversibly cleave the carbonate protecting groups while simultaneously oxidizing the internucleotide phosphite triester linkage to a phosphodiester linkage. The procedure may be carried out in aqueous solution at neutral to mildly basic pH. The method eliminates the need for separate deprotection and oxidation steps, and, since the use of acid to remove protecting groups is unnecessary, acid-induced depurination is avoided. Fluorescent or other readily detectable carbonate protecting groups can be used, enabling monitoring of individual reaction steps during oligonucleotide synthesis. The invention is particularly useful in the highly parallel, microscale synthesis of oligonucleotides.

Methods of synthesizing oligonucleotides using carbonate protecting groups and alpha-effect nucleophile deprotection

Aspects of the invention include 2' protected nucleoside monomers that are protected at the 2&#x2032; site with orthoester-type protecting groups. The 2&#x2032; protected monomers also include a second, aryl carbonate-type, protecting group. Aspects of the invention further include nucleic acids that include the protecting groups of the invention, as well as methods of synthesizing nucleic acids using the protecting groups of the invention.

Protecting groups for RNA synthesis

Nucleotide monomers, polynucleotides, methods of making each, and methods of deprotecting each, are disclosed. An embodiment of the nucleotide monomer, among others, includes a nucleotide monomer having a heterobase protecting group selected from structures I through III as described herein. An embodiment of the polynucleotide, among others, includes a plurality of nucleotide moieties having a heterobase protecting group selected from one of structures I through III as described herein.

Monomer compositions for the synthesis of polynucleotides, methods of synthesis, and methods of deprotection

Embodiments of the invention include nucleotide and nucleoside monomers protected at the 5'- or 3&#x2032;-hydroxyls with thioether substituted aryl carbonate protecting groups. In certain cases, the carbonate protecting groups include an aryl moiety, e.g., a phenyl group, attached to the carbonate, where the aryl moiety further includes a thioether group, e.g., an alkyl or aryl thioether group, bound directly to the aryl ring. Aspects of the invention further include methods of synthesizing nucleic acids, e.g., oligonucleotides, using such protected nucleoside monomer monomers, as well as nucleic acids produced using methods of the invention and compositions thereof.

Thioether substituted aryl carbonate protecting groups

Growing community of inventors

Loveland, CO, United States of America

Marvin H Caruthers