CN108472385A - 与钉合或拼接肽缀合的生物活性化合物 - Google Patents
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| GB2545898B (en) | 2015-12-21 | 2019-10-09 | Sutura Therapeutics Ltd | Improved drug delivery by conjugating oligonucleotides to stitched/stapled peptides |
| MA45328A (fr) | 2016-04-01 | 2019-02-06 | Avidity Biosciences Llc | Compositions acide nucléique-polypeptide et utilisations de celles-ci |
| MX2019008199A (es) | 2017-01-06 | 2019-11-25 | Avidity Biosciences Llc | Composiciones de acido nucleico polipeptido y metodos de induccion de la omision de exon. |
| GB2563875B (en) * | 2017-06-28 | 2020-08-19 | Sutura Therapeutics Ltd | Improvements in drug delivery |
| GB201711809D0 (en) | 2017-07-21 | 2017-09-06 | Governors Of The Univ Of Alberta | Antisense oligonucleotide |
| WO2019070962A1 (en) | 2017-10-04 | 2019-04-11 | Ohio State Innovation Foundation | BICYCLIC PEPTIDE INHIBITORS |
| US11510991B2 (en) | 2017-10-27 | 2022-11-29 | Ohio State Innovation Foundation | Polypeptide conjugates for intracellular delivery of stapled peptides |
| US11793884B2 (en) | 2018-01-29 | 2023-10-24 | Ohio State Innovation Foundation | Cyclic peptidyl inhibitors of CAL-PDZ binding domain |
| CA3089279A1 (en) | 2018-02-07 | 2019-08-15 | Dana-Farber Cancer Institute, Inc. | Cell-permeable stapled peptide modules for cellular delivery |
| US11459304B2 (en) | 2018-08-31 | 2022-10-04 | Massachusetts Institute Of Technology | Ionizable lipidoids and their uses |
| EP3962933A1 (en) * | 2019-04-18 | 2022-03-09 | Dana-Farber Cancer Institute, Inc. | Selective targeting of ubiquitin- and ubiquitin-like e1-activating enzymes by structurally-stabilized peptides |
| KR102499670B1 (ko) * | 2019-06-17 | 2023-02-20 | 고려대학교 산학협력단 | 라이신 치환을 포함하는 Romo1 유래 항균 펩타이드 및 그 변이체 |
| KR102521182B1 (ko) * | 2020-11-06 | 2023-04-12 | 서울대학교산학협력단 | 결핵균 독소-항독소 시스템을 표적으로 하는 항균 스테이플 펩타이드 및 이의 용도 |
| WO2024069229A2 (en) | 2022-08-03 | 2024-04-04 | Sutura Therapeutics Ltd | Biologically active compounds |
| WO2025027389A1 (en) | 2023-08-03 | 2025-02-06 | Sutura Therapeutics Limited | Biologically active compounds comprising a stapled or stitched peptide |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101790385A (zh) * | 2007-07-12 | 2010-07-28 | 普罗森那技术公司 | 用于使化合物靶向多种选定器官、组织或肿瘤细胞的分子 |
| CN103121959A (zh) * | 2011-11-21 | 2013-05-29 | 昆山市工业技术研究院小核酸生物技术研究所有限责任公司 | 化合物和核酸复合分子与核酸复合物及其制备方法和应用 |
| WO2013150338A1 (en) * | 2012-04-04 | 2013-10-10 | Centre National De La Recherche Scientifique | Stapled cell penetrating peptides for intracellular delivery of molecules |
| CN103626850A (zh) * | 2013-04-03 | 2014-03-12 | 安徽省新星药物开发有限责任公司 | 具有细胞穿透功能的多肽及其在药物递送中的用途 |
| CN103998458A (zh) * | 2011-08-30 | 2014-08-20 | 医学研究理事会 | 具有中央疏水域的细胞穿透肽 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE192465T1 (de) * | 1987-10-28 | 2000-05-15 | Florey Howard Inst | Oligonucleotid-polyamid konjugate |
| PL2203173T3 (pl) * | 2007-10-26 | 2016-06-30 | Academisch Ziekenhuis Leiden | Środki i sposoby przeciwdziałania zaburzeniom mięśni |
| US20110250685A1 (en) | 2008-06-03 | 2011-10-13 | Nash Huw M | Compositions and methods for enhancing cellular transport of biomolecules |
| KR20180118828A (ko) | 2008-10-24 | 2018-10-31 | 사렙타 쎄러퓨틱스 인코퍼레이티드 | Dmd를 위한 다중 엑손 스키핑 조성물 |
| WO2010123369A1 (en) * | 2009-04-24 | 2010-10-28 | Prosensa Technologies B.V. | Oligonucleotide comprising an inosine for treating dmd |
| WO2011008260A2 (en) | 2009-07-13 | 2011-01-20 | President And Fellows Of Harvard College | Bifunctional stapled polypeptides and uses thereof |
| WO2011111874A1 (ja) | 2010-03-11 | 2011-09-15 | 独立行政法人理化学研究所 | 細胞膜透過性ダンベル型rnaおよびその製造方法 |
| EP3231446A1 (en) * | 2010-04-19 | 2017-10-18 | Nlife Therapeutics S.L. | Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types |
| WO2012150960A1 (en) | 2011-05-05 | 2012-11-08 | Avi Biopharma, Inc. | Peptide oligonucleotide conjugates |
| WO2014053879A1 (en) * | 2012-10-04 | 2014-04-10 | Centre National De La Recherche Scientifique | Cell penetrating peptides for intracellular delivery of molecules |
| CA2889608A1 (en) * | 2012-10-26 | 2014-05-01 | Nlife Therapeutics, S.L. | Compositions and methods for selective delivery of oligonucleotide molecules to cell types |
| EP3297649B1 (en) * | 2015-05-19 | 2023-10-11 | Sarepta Therapeutics, Inc. | Peptide oligonucleotide conjugates |
| SG10201912066SA (en) | 2015-07-15 | 2020-02-27 | Protagonist Therapeutics Inc | Peptide inhibitors of interleukin-23 receptor and their use to treat inflammatory diseases |
| GB2545898B (en) | 2015-12-21 | 2019-10-09 | Sutura Therapeutics Ltd | Improved drug delivery by conjugating oligonucleotides to stitched/stapled peptides |
| GB2563875B (en) | 2017-06-28 | 2020-08-19 | Sutura Therapeutics Ltd | Improvements in drug delivery |
-
2015
- 2015-12-21 GB GB1522548.5A patent/GB2545898B/en not_active Expired - Fee Related
-
2016
- 2016-12-21 AU AU2016375869A patent/AU2016375869B2/en not_active Ceased
- 2016-12-21 WO PCT/GB2016/054028 patent/WO2017109494A1/en not_active Ceased
- 2016-12-21 EP EP16822244.6A patent/EP3393520A1/en not_active Withdrawn
- 2016-12-21 CA CA3007910A patent/CA3007910A1/en active Pending
- 2016-12-21 JP JP2018550872A patent/JP2019508481A/ja active Pending
- 2016-12-21 CN CN201680073127.3A patent/CN108472385A/zh active Pending
- 2016-12-21 US US16/061,548 patent/US11541124B2/en active Active
- 2016-12-21 BR BR112018012641A patent/BR112018012641A2/pt active Search and Examination
- 2016-12-21 KR KR1020187020172A patent/KR20180091920A/ko active Pending
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2022
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-
2023
- 2023-02-02 JP JP2023014917A patent/JP2023055874A/ja active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101790385A (zh) * | 2007-07-12 | 2010-07-28 | 普罗森那技术公司 | 用于使化合物靶向多种选定器官、组织或肿瘤细胞的分子 |
| CN103998458A (zh) * | 2011-08-30 | 2014-08-20 | 医学研究理事会 | 具有中央疏水域的细胞穿透肽 |
| CN103121959A (zh) * | 2011-11-21 | 2013-05-29 | 昆山市工业技术研究院小核酸生物技术研究所有限责任公司 | 化合物和核酸复合分子与核酸复合物及其制备方法和应用 |
| WO2013150338A1 (en) * | 2012-04-04 | 2013-10-10 | Centre National De La Recherche Scientifique | Stapled cell penetrating peptides for intracellular delivery of molecules |
| CN103626850A (zh) * | 2013-04-03 | 2014-03-12 | 安徽省新星药物开发有限责任公司 | 具有细胞穿透功能的多肽及其在药物递送中的用途 |
Non-Patent Citations (2)
| Title |
|---|
| 杨铭: "3.连接臂link的选择", 《药物研究中的分子识别》 * |
| 王晓良: "二、订书肽的功能与应用", 《应用分子药理学》 * |
Also Published As
| Publication number | Publication date |
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| AU2016375869A1 (en) | 2018-08-09 |
| GB2545898B (en) | 2019-10-09 |
| US20200353092A1 (en) | 2020-11-12 |
| GB2545898A (en) | 2017-07-05 |
| JP2019508481A (ja) | 2019-03-28 |
| WO2017109494A1 (en) | 2017-06-29 |
| US11541124B2 (en) | 2023-01-03 |
| US11944688B2 (en) | 2024-04-02 |
| AU2016375869B2 (en) | 2023-07-13 |
| US20230158166A1 (en) | 2023-05-25 |
| KR20180091920A (ko) | 2018-08-16 |
| BR112018012641A2 (pt) | 2018-12-04 |
| CA3007910A1 (en) | 2017-06-29 |
| GB201522548D0 (en) | 2016-02-03 |
| EP3393520A1 (en) | 2018-10-31 |
| JP2023055874A (ja) | 2023-04-18 |
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