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Structure-based design of a Cortistatin analog with improved immunoregulatory activity against inflammatory bowel disease (IBD)

Álvaro Rol, View ORCID ProfileToni Todorovski, View ORCID ProfilePau Martin-Malpartida, Anna Escolà, View ORCID ProfileElena Gonzalez-Rey, View ORCID ProfileEric Aragón, View ORCID ProfileXavier Verdaguer, Mariona Vallès-Miret, View ORCID ProfileJosep Farrera-Sinfreu, View ORCID ProfileEduard Puig, Jimena Fernández-Carneado, Berta Ponsati, View ORCID ProfileMario Delgado, View ORCID ProfileAntoni Riera, View ORCID ProfileMaria J. Macias
doi: https://doi.org/10.1101/839787
Álvaro Rol
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
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Toni Todorovski
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
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  • ORCID record for Toni Todorovski
Pau Martin-Malpartida
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
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Anna Escolà
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
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Elena Gonzalez-Rey
bInstituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Avda. Conocimiento S/N, Parque Tecnológico Ciencias de la Salud, 18100 Armilla, Granada, Spain
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Eric Aragón
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
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Xavier Verdaguer
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
cDepartament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain
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Mariona Vallès-Miret
dBCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars, Sector II. Ctra. Comarcal 244, Km. 22, 08777 Sant Quintí de Mediona, Barcelona08777, Spain
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Josep Farrera-Sinfreu
dBCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars, Sector II. Ctra. Comarcal 244, Km. 22, 08777 Sant Quintí de Mediona, Barcelona08777, Spain
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Eduard Puig
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
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Jimena Fernández-Carneado
dBCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars, Sector II. Ctra. Comarcal 244, Km. 22, 08777 Sant Quintí de Mediona, Barcelona08777, Spain
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Berta Ponsati
dBCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars, Sector II. Ctra. Comarcal 244, Km. 22, 08777 Sant Quintí de Mediona, Barcelona08777, Spain
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Mario Delgado
bInstituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Avda. Conocimiento S/N, Parque Tecnológico Ciencias de la Salud, 18100 Armilla, Granada, Spain
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  • For correspondence: mdelgado@ipb.csic.es antoni.riera@irbbarcelona.org maria.macias@irbbarcelona.org
Antoni Riera
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
cDepartament de Química Inorgànica i Orgànica, Secció de Química Orgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona, Spain
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  • For correspondence: mdelgado@ipb.csic.es antoni.riera@irbbarcelona.org maria.macias@irbbarcelona.org
Maria J. Macias
aInstitute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, Barcelona 08028, Spain
eInstitució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys, 23, Barcelona 08010, Spain
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  • For correspondence: mdelgado@ipb.csic.es antoni.riera@irbbarcelona.org maria.macias@irbbarcelona.org
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Summary

Ulcerative colitis and Crohn’s disease are inflammatory bowel diseases (IBD) that lead to chronic inflammations of the gastrointestinal tract due to an abnormal response of the immune system. Finding new effective drugs to tackle IBD represents a major therapeutic concern since IBD incidence and prevalence is increasing worldwide. Recent studies positioned Cortistatin (CST) as a candidate for IBD treatment due to its anti-inflammatory and immunomodulatory activity. Here, we studied the structural properties of CST using NMR and synthesized and characterized new analogs displaying enriched populations of some native conformations. One of them, Analog 5, preserved the activity against IBD with an increased half-life in serum, overcoming the native hormone limitation and opening the door for the use of CST analogs as therapeutic agents. This work represents a new approach to the rational design of molecules to treat IBD and a possibility for patients that fail to respond to other therapies.

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Posted November 20, 2019.
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Structure-based design of a Cortistatin analog with improved immunoregulatory activity against inflammatory bowel disease (IBD)
Álvaro Rol, Toni Todorovski, Pau Martin-Malpartida, Anna Escolà, Elena Gonzalez-Rey, Eric Aragón, Xavier Verdaguer, Mariona Vallès-Miret, Josep Farrera-Sinfreu, Eduard Puig, Jimena Fernández-Carneado, Berta Ponsati, Mario Delgado, Antoni Riera, Maria J. Macias
bioRxiv 839787; doi: https://doi.org/10.1101/839787
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Structure-based design of a Cortistatin analog with improved immunoregulatory activity against inflammatory bowel disease (IBD)
Álvaro Rol, Toni Todorovski, Pau Martin-Malpartida, Anna Escolà, Elena Gonzalez-Rey, Eric Aragón, Xavier Verdaguer, Mariona Vallès-Miret, Josep Farrera-Sinfreu, Eduard Puig, Jimena Fernández-Carneado, Berta Ponsati, Mario Delgado, Antoni Riera, Maria J. Macias
bioRxiv 839787; doi: https://doi.org/10.1101/839787

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