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1. 发明授权

US10138268B2 Peptide fragment condensation and cyclisation using a subtilisin variant with improved synthesis over hydrolysis ratio 有权
公开(公告)号：US10138268B2
公开(公告)日：2018-11-27
申请号：US15517812
申请日：2015-10-09
申请人： ENZYPEP B.V.
发明人： Peter Jan Leonard Mario Quaedflieg , Timo Nuijens , Jan Metske Van Der Laan , Dirk Barend Janssen , Ana Toplak , Bian Wu
IPC分类号： C12N9/48 , C07K1/02 , C12P21/02 , C12N9/54 , C07K1/36
摘要： The invention relates to a method for enzymatically synthesizing an (oligo)peptide, comprising coupling (a) an (oligo)peptide C-terminal ester or thioester and (b) an (oligo)peptide nucleophile having an N-terminally unprotected amine, wherein the coupling is carried out in a fluid comprising water, and wherein the coupling is catalyzed by a subtilisin BPN′ variant or a homo-log thereof, which comprises the following mutations compared to subtilisin BPN′ represented by SEQUENCE ID NO: 2 or a homolog sequence thereof: a deletion of the amino acids corresponding to positions 75-83; a mutation at the amino acid position corresponding to S221, the mutation being S221C or S221 selenocysteine; preferably a mutation at the amino acid position corresponding to P225 wherein the amino acid positions are defined according to the sequence of subtilisin BPN′ represented by SEQUENCE ID NO: 2. Further, the invention relates to an enzyme suitable for use as a catalyst in a method of the invention.

2. 发明授权

US10920258B2 Chemo-enzymatic synthesis of semaglutide, liraglutide and GLP-1 有权
公开(公告)号：US10920258B2
公开(公告)日：2021-02-16
申请号：US16783570
申请日：2020-02-06
申请人： ENZYPEP B.V.
发明人： Timo Nuijens , Ana Toplak , Peter Jan Leonard Mario Quaedflieg
IPC分类号： A61K38/00 , C12P21/02 , C12N9/50 , C12N9/00
摘要： A method for synthesizing a peptide having the sequence His-X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly is disclosed. The method includes enzymatically coupling: (a) a peptide C-terminal ester or thioester having a first peptide fragment with the sequence His-X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-(thio)ester; and (b) a peptide nucleophile having an N-terminally unprotected amine having a second peptide fragment with the sequence H-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly; wherein: X is Ala or an α-amino-isobutyric acid (Aib) residue; Y is Lys, which Lys has a free side-chain ε-amino group or of which Lys the side-chain ε-amino group is protected with a protective group or of which Lys the side-chain ε-amino group is functionalized with an amino acid or another functional group; and Z is Arg or Lys.

3. 发明授权

US10883132B2 Chemo-enzymatic synthesis of Semaglutide, Liraglutide and GLP-1 有权
公开(公告)号：US10883132B2
公开(公告)日：2021-01-05
申请号：US16463471
申请日：2019-03-11
申请人： ENZYPEP B.V.
发明人： Timo Nuijens , Ana Toplak , Peter Jan Leonard Mario Quaedflieg
IPC分类号： A61K38/00 , C12P21/02 , C12N9/50 , C12N9/00
摘要： A method for synthesizing a peptide having the sequence His-X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly is disclosed. The method includes enzymatically coupling: (a) a peptide C-terminal ester or thioester having a first peptide fragment with the sequence His-X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-(thio)ester; and (b) a peptide nucleophile having an N-terminally unprotected amine having a second peptide fragment with the sequence H-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly; wherein: X is Ala or an α-amino-isobutyric acid (Aib) residue; Y is Lys, which Lys has a free side-chain ε-amino group or of which Lys the side-chain ε-amino group is protected with a protective group or of which Lys the side-chain ε-amino group is functionalized with an amino acid or another functional group; and Z is Arg or Lys.

4. 发明授权

US10336994B2 Subtilisin variants having a mutation in the S2 or S2# pocket 有权
公开(公告)号：US10336994B2
公开(公告)日：2019-07-02
申请号：US16193963
申请日：2018-11-16
申请人： EnzyPep B.V.
发明人： Ana Toplak , Timo Nuijens , Peter Jan Leonard Mario Quaedflieg
IPC分类号： C12N9/52 , C12P21/02 , C07K1/02 , C12N9/54 , C12P21/06
摘要： The invention relates to a subtilisin BPN′ variant or homolog thereof, having the following mutations compared to subtilisin BPN′ represented by SEQUENCE ID NO: 2 or a homolog sequence thereof:—a deletion of the amino acids corresponding to positions 75-83;—a mutation at the amino acid position corresponding to S221, the mutation corresponding to S221C or S221 selenocysteine, preferably S221C;—at least one further mutation selected from the group consisting of amino acid positions corresponding to F189W, F189Y, S33D, S33T, N218D, N218T, N218E, N62D, N62S, N62W, and N62Y; preferably a mutation at the amino acid position corresponding to P225; wherein the amino acid positions are defined according to the sequence of subtilisin BPN′ represented by SEQUENCE ID NO: 2. The invention further relates to enzymatically synthesizing a peptide.

5. 发明授权

US10253061B2 Peptide fragment condensation and cyclisation using a subtilisin variant with improved synthesis over hydrolysis ratio 有权
公开(公告)号：US10253061B2
公开(公告)日：2019-04-09
申请号：US16162885
申请日：2018-10-17
申请人： ENZYPEP B.V.
发明人： Peter Jan Leonard Mario Quaedflieg , Timo Nuijens , Jan Metske Van Der Laan , Dirk Barend Janssen , Ana Toplak , Bian Wu
IPC分类号： C12N9/48 , C07K1/02 , C12P21/02 , C12N9/54 , C07K1/36
摘要： The invention relates to a method for enzymatically synthesizing an (oligo)peptide, comprising coupling (a) an (oligo)peptide C-terminal ester or thioester and (b) an (oligo)peptide nucleophile having an N-terminally unprotected amine, wherein the coupling is carried out in a fluid comprising water, and wherein the coupling is catalyzed by a subtilisin BPN′ variant or a homolog thereof, which comprises the following mutations compared to subtilisin BPN′ represented by SEQUENCE ID NO: 2 or a homolog sequence thereof: a deletion of the amino acids corresponding to positions 75-83; a mutation at the amino acid position corresponding to S221, the mutation being S221C or S221 selenocysteine; preferably a mutation at the amino acid position corresponding to P225 wherein the amino acid positions are defined according to the sequence of subtilisin BPN′ represented by SEQUENCE ID NO: 2. Further, the invention relates to an enzyme suitable for use as a catalyst in a method of the invention.

6. 发明申请

US20190078069A1 SUBTILISIN VARIANTS HAVING A MUTATION IN THE S2 OR S2′ POCKET 审中-公开
公开(公告)号：US20190078069A1
公开(公告)日：2019-03-14
申请号：US16193963
申请日：2018-11-16
申请人： EnzyPep B.V.
发明人： Ana Toplak , Timo Nuijens , Peter Jan Leonard Mario Quaedflieg
IPC分类号： C12N9/52 , C12P21/02 , C12P21/06
CPC分类号： C12N9/52 , C07K1/026 , C12N9/54 , C12P21/02 , C12P21/06 , C12Y304/21062
摘要： The invention relates to a subtilisin BPN′ variant or homologue thereof, having the following mutations compared to subtilisin BPN′ represented by SEQUENCE ID NO: 2 or a homologue sequence thereof:—a deletion of the amino acids corresponding to positions 75-83;—a mutation at the amino acid position corresponding to S221, the mutation corresponding to S221C or S221 selenocysteine, preferably S221C;—at least one further mutation selected from the group consisting of amino acid positions corresponding to F189W, F189Y, S33D, S33T, N218D, N218T, N218E, N62D, N62S, N62W, and N62Y; preferably a mutation at the amino acid position corresponding to P225; wherein the amino acid positions are defined according to the sequence of subtilisin BPN′ represented by SEQUENCE ID NO: 2. The invention further relates to enzymatically synthesizing a peptide.

7. 发明授权

US10858414B2 Chemo-enzymatic synthesis of semaglutide, liraglutide and GLP-1 有权
公开(公告)号：US10858414B2
公开(公告)日：2020-12-08
申请号：US16349106
申请日：2019-03-08
申请人： ENZYPEP B.V.
发明人： Timo Nuijens , Ana Toplak , Peter Jan Leonard Mario Quaedflieg
IPC分类号： C07K14/605 , C12N9/54
摘要： The invention relates to a method for preparing a coupling product having the sequence Pq-Wv-His-X-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly. The method includes enzymatically coupling (a) a peptide C-terminal ester or thioester having a first peptide fragment represented by the formula Pq-Wv-His-X-Glu-(thio)ester; and (b) a peptide nucleophile having an N-terminally unprotected amine having a second peptide fragment with the sequence H-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Y-Glu-Phe-Ile-Ala-Trp-Leu-Val-Z-Gly-Arg-Gly wherein P represents a protective group at the N-terminal α-amino function of the peptide C-terminal ester or thioester and q is an integer having a value of 1 or 0; W represents one or more amino acid residues, which may be the same or different and v is an integer having a value of 1 or more representing the number of amino acid residues W; X is Ala or an α-amino-isobutyric acid unit (Aib); Y is Lys, which Lys has a free side-chain ε-amino group or a side-chain ε-amino group that is protected with a protective group or a side-chain ε-amino group that is functionalized with an amino acid or another functional group; and Z is Arg or Lys.

8. 发明授权

US10752931B2 Designing an enzymatic peptide fragment condensation strategy 有权
公开(公告)号：US10752931B2
公开(公告)日：2020-08-25
申请号：US15741080
申请日：2016-07-08
申请人： EnzyPep B.V.
发明人： Timo Nuijens , Peter Jan Leonard Mario Quaedflieg
IPC分类号： C12N9/48 , C12N9/54 , C12P21/02 , C12Q1/37 , G01N33/68 , C12N9/64 , C07K1/02
摘要： The invention further relates to a process for the enzymatic synthesis of an (oligo)peptide. The invention relates to a method for designing an enzymatic synthesis process of an (oligo)peptide, comprising identifying two or more (oligo)peptide fragments of an (oligo)peptide, which fragments are (oligo)peptides suitable for preparing the (oligo)peptide by enzymatic condensation of the two or more peptide fragments using a ligase. The invention relates to a method for designing an enzymatic synthesis process of a cyclic (oligo)peptide, comprising identifying a non-cyclic (oligo)peptide from which the cyclic (oligo)peptide can be prepared by cyclisation, catalysed by a cyclase. The invention further relates to a process for the enzymatic synthesis of an (oligo)peptide.

9. 发明申请

US20180187231A1 DESIGNING AN ENZYMATIC PEPTIDE FRAGMENT CONDENSATION STRATEGY 审中-公开
公开(公告)号：US20180187231A1
公开(公告)日：2018-07-05
申请号：US15741080
申请日：2016-07-08
申请人： EnzyPep B.V.
发明人： Timo Nuijens , Peter Jan Leonard Mario Quaedflieg
IPC分类号： C12P21/02 , C07K1/02 , C12Q1/37 , C12N9/64 , G01N33/68
摘要： The invention further relates to a process for the enzymatic synthesis of an (oligo)peptide. The invention relates to a method for designing an enzymatic synthesis process of an (oligo)peptide, comprising identifying two or more (oligo)peptide fragments of an (oligo)peptide, which fragments are (oligo)peptides suitable for preparing the (oligo)peptide by enzymatic condensation of the two or more peptide fragments using a ligase. The invention relates to a method for designing an enzymatic synthesis process of a cyclic (oligo)peptide, comprising identifying a non-cyclic (oligo)peptide from which the cyclic (oligo)peptide can be prepared by cyclisation, catalysed by a cyclase. The invention further relates to a process for the enzymatic synthesis of an (oligo)peptide.

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