Structure-guided Discovery of Dual-recognition Chemibodies

Abstract Small molecules and antibodies each have advantages and limitations as therapeutics. Here, we present for the first time to our knowledge, the structure-guided design of “chemibodies” as small molecule-antibody hybrids that offer dual recognition of a single target by both a small molecule...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Alan C. Cheng, Elizabeth M. Doherty, Sheree Johnstone, Erin F. DiMauro, Jennifer Dao, Abhinav Luthra, Jay Ye, Jie Tang, Thomas Nixey, Xiaoshan Min, Philip Tagari, Les P. Miranda, Zhulun Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/03c054e59aee48aa9fd15ab0e960b901
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:03c054e59aee48aa9fd15ab0e960b901
record_format	dspace
spelling	oai:doaj.org-article:03c054e59aee48aa9fd15ab0e960b9012021-12-02T15:08:00ZStructure-guided Discovery of Dual-recognition Chemibodies10.1038/s41598-018-25848-02045-2322https://doaj.org/article/03c054e59aee48aa9fd15ab0e960b9012018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25848-0https://doaj.org/toc/2045-2322Abstract Small molecules and antibodies each have advantages and limitations as therapeutics. Here, we present for the first time to our knowledge, the structure-guided design of “chemibodies” as small molecule-antibody hybrids that offer dual recognition of a single target by both a small molecule and an antibody, using DPP-IV enzyme as a proof of concept study. Biochemical characterization demonstrates that the chemibodies present superior DPP-IV inhibition compared to either small molecule or antibody component alone. We validated our design by successfully solving a co-crystal structure of a chemibody in complex with DPP-IV, confirming specific binding of the small molecule portion at the interior catalytic site and the Fab portion at the protein surface. The discovery of chemibodies presents considerable potential for novel therapeutics that harness the power of both small molecule and antibody modalities to achieve superior specificity, potency, and pharmacokinetic properties.Alan C. ChengElizabeth M. DohertySheree JohnstoneErin F. DiMauroJennifer DaoAbhinav LuthraJay YeJie TangThomas NixeyXiaoshan MinPhilip TagariLes P. MirandaZhulun WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alan C. Cheng Elizabeth M. Doherty Sheree Johnstone Erin F. DiMauro Jennifer Dao Abhinav Luthra Jay Ye Jie Tang Thomas Nixey Xiaoshan Min Philip Tagari Les P. Miranda Zhulun Wang Structure-guided Discovery of Dual-recognition Chemibodies
description	Abstract Small molecules and antibodies each have advantages and limitations as therapeutics. Here, we present for the first time to our knowledge, the structure-guided design of “chemibodies” as small molecule-antibody hybrids that offer dual recognition of a single target by both a small molecule and an antibody, using DPP-IV enzyme as a proof of concept study. Biochemical characterization demonstrates that the chemibodies present superior DPP-IV inhibition compared to either small molecule or antibody component alone. We validated our design by successfully solving a co-crystal structure of a chemibody in complex with DPP-IV, confirming specific binding of the small molecule portion at the interior catalytic site and the Fab portion at the protein surface. The discovery of chemibodies presents considerable potential for novel therapeutics that harness the power of both small molecule and antibody modalities to achieve superior specificity, potency, and pharmacokinetic properties.
format	article
author	Alan C. Cheng Elizabeth M. Doherty Sheree Johnstone Erin F. DiMauro Jennifer Dao Abhinav Luthra Jay Ye Jie Tang Thomas Nixey Xiaoshan Min Philip Tagari Les P. Miranda Zhulun Wang
author_facet	Alan C. Cheng Elizabeth M. Doherty Sheree Johnstone Erin F. DiMauro Jennifer Dao Abhinav Luthra Jay Ye Jie Tang Thomas Nixey Xiaoshan Min Philip Tagari Les P. Miranda Zhulun Wang
author_sort	Alan C. Cheng
title	Structure-guided Discovery of Dual-recognition Chemibodies
title_short	Structure-guided Discovery of Dual-recognition Chemibodies
title_full	Structure-guided Discovery of Dual-recognition Chemibodies
title_fullStr	Structure-guided Discovery of Dual-recognition Chemibodies
title_full_unstemmed	Structure-guided Discovery of Dual-recognition Chemibodies
title_sort	structure-guided discovery of dual-recognition chemibodies
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/03c054e59aee48aa9fd15ab0e960b901
work_keys_str_mv	AT alanccheng structureguideddiscoveryofdualrecognitionchemibodies AT elizabethmdoherty structureguideddiscoveryofdualrecognitionchemibodies AT shereejohnstone structureguideddiscoveryofdualrecognitionchemibodies AT erinfdimauro structureguideddiscoveryofdualrecognitionchemibodies AT jenniferdao structureguideddiscoveryofdualrecognitionchemibodies AT abhinavluthra structureguideddiscoveryofdualrecognitionchemibodies AT jayye structureguideddiscoveryofdualrecognitionchemibodies AT jietang structureguideddiscoveryofdualrecognitionchemibodies AT thomasnixey structureguideddiscoveryofdualrecognitionchemibodies AT xiaoshanmin structureguideddiscoveryofdualrecognitionchemibodies AT philiptagari structureguideddiscoveryofdualrecognitionchemibodies AT lespmiranda structureguideddiscoveryofdualrecognitionchemibodies AT zhulunwang structureguideddiscoveryofdualrecognitionchemibodies
_version_	1718388297103835136

Structure-guided Discovery of Dual-recognition Chemibodies

Ejemplares similares