Neuregulin variants and methods of screening and using thereof 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
US2016297859 A1 2016-10-13 [US20160297859] / 2016-10-13
申请号/申请日
2016US-15097198 / 2016-04-12
发明人
ZHOU MINGDONG;
申请人
ZENSUN (SHANGHAI) SCI & TECH;
主分类号
IPC分类号
C07K-014/475G06F-019/16G06F-019/18
摘要
(US20160297859) The present invention provides polypeptide variants of neuregulin-1β (NRG-1β) that have enhanced or decreased binding affinity to ErbB3 and/or ErbB4.  The invention also provides methods of screening and producing polypeptide variants of NRG-1β and methods of using polypeptide variants of NRG-1β for treating diseases.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2005US-11293879 2005-12-02 2006WO-CN03240 2006-12-04 2008US-12095904 2008-12-29 2013US-13848616 2013-03-21 2016US-15097198 2016-04-12
主权利要求
(US20160297859) 1. A polypeptide variant of neuregulin-1beta comprising aminoacid sequence shown in SEQ ID NO:1, wherein the polypeptide variant comprises a different aminoacid than that in SEQ ID NO:1, wherein the polypeptide variant has an enhanced binding affinity to ErbB3 compared to polypeptide of SEQ ID NO:1, and wherein at residue 25 said different aminoacid is A, C, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y; or at residue 35 said different aminoacid is A, C, D, E, F, G, H, I, L, N, M, P, Q, R, S, T, V, W, or Y; or at residue 46 said different aminoacid is A, C, D, E, F, G, H, I, K, L, M, N, P, R, S, T, V, W, or Y. 17. A polypeptide variant of neuregulin-1beta comprising aminoacid sequence shown in SEQ ID NO: 1, wherein the polypeptide variant comprises a different aminoacid than that in SEQ ID NO: 1, wherein the polypeptide variant has an enhanced binding affinity to ErbB4 compared to polypeptide of SEQ ID NO:1, and wherein at residue 16 said different aminoacid is A, C, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y; at residue 31 said different aminoacid is A, C, D, E, F, G, H, I, K, L, M, N, P, Q, S, T, V, W, or Y; or at residue 47 said different aminoacid is A, C, D, E, F, G, H, I, K, L, M, P, Q, R, S, T, V, W, or Y. 38. A method for screening a polypeptide variant of neuregulin-1beta having enhanced binding affinity selective to ErbB3, which method comprises: (a) establishing a three-dimensional structure of a neuregulin-1beta or a fragment thereof, an ErbB3, an ErbB4, a complex of the neuregulin-1beta or the fragment thereof and the ErbB3, and a complex of the neuregulin-1beta or the fragment thereof and the ErbB4 by homology modeling; (b) establishing data of conformational changes and stability of the complex of the neuregulin-1beta or the fragment thereof and the ErbB3, and the complex of the neuregulin-1beta or the fragment thereof and the ErbB4 in solution by molecular dynamics simulation method; (c) calculating subtotal binding free energy (<G subtotal wild type) of the neuregulin-1beta or the fragment thereof with the ErbB3 or the ErbB4 by Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) method; (d) calculating subtotal binding free energy (<Gsubtotal alanine substituted variant) of an alanine substituted variant of the neuregulin-1beta or the fragment thereof with the ErbB3 or the ErbB4 by Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) method, wherein the alanine substituted variant comprises an aminoacid of the neuregulin-1beta or the fragment thereof substituted by an alanine; (e) calculating <<Gsubtotal=<Gsubttotal wild type-<Gsubtotal alanine substituted variants (f) selecting alanine substituted variant that has a positive value of <<Gsubtotal for the complex of the neuregulin-1beta or the fragment thereof and the ErbB3, and has a negative value or a value of about zero for <<Gsubtotal form the complex of the neuregulin-1beta or the fragment thereof and the ErbB4; whereby a polypeptide variant of neuregulin-1beta that has enhanced binding affinity selective to ErbB3 is identified.
法律状态
(US20160297859) LEGAL DETAILS FOR US2016297859  Actual or expected expiration date=2028-12-29    Legal state=ALIVE    Status=PENDING     Event publication date=2016-04-12  Event code=US/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=US US15097198  Application date=2016-04-12  Standardized application number=2016US-15097198     Event publication date=2016-04-12  Event code=US/EXMR  Event type=Administrative notifications  USPTO Examiner Name Primary Examiner: MACFARLANE, STACEY NEE    Event publication date=2016-04-12  Event code=US/ART  Event type=Administrative notifications  USPTO Art Group  ART=1649     Event publication date=2016-04-12  Event code=US/DK  Event type=Examination events  Attorney Docket Number Docket Nbr: 11748-060-999 Customer Nbr: 20583    Event publication date=2016-04-12  Event code=US/ENT  Event type=Administrative notifications  Business Entity Status: SMALL    Event publication date=2016-04-12  Event code=US/AIA  Event type=Administrative notifications  First Inventor File Indicated:  AIA=No     Event publication date=2016-04-12  Event code=US/ENTYSTA  Event type=Administrative notifications  Entity Status Set to Undiscounted    Event publication date=2016-04-20  Event code=US/APPINC  Event type=Examination events  Event type=OAO  Notice Mailed--Application Incomplete--Filing Date Assigned    Event publication date=2016-04-20  Event code=US/APPFILEREC  Event type=Administrative notifications  Event type=OAO  Filing Receipt    Event publication date=2016-04-20  Event code=US/SMALL  Event type=Administrative notifications  Appl Has Filed a Verified Statement of Micro to Small Entity Status    Event publication date=2016-06-20  Event code=US/PTARDY  Event indicator=Pos  Event type=Examination events  Patent Term Adjustment - Ready for Examination    Event publication date=2016-07-01  Event code=US/RECEIPTUP  Event type=Administrative notifications  Event type=OAO  Filing Receipt - Updated    Event publication date=2016-07-05  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner in GAU    Event publication date=2016-10-13  Event code=US/A1  Event type=Examination events  Application published  Publication country=US  Publication number=US2016297859  Publication stage Code=A1  Publication date=2016-10-13  Standardized publication number=US20160297859     Event publication date=2016-10-13  Event code=US/PGPUBN  Event indicator=Pos  Event type=Examination events  Event type=OAO  PG-Pub Issue Notification    Event publication date=2016-12-13  Event code=US/RECEIPTCOR  Event type=Administrative notifications  Event type=OAO  Filing Receipt - Corrected    Event publication date=2017-08-14  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection
专利类型码
A1
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