Conformational ligand-directed targeting of calcium-dependent receptors in acute trauma
1
Issued Date
2025-01-01
Resource Type
ISSN
26666359
eISSN
26666340
Scopus ID
2-s2.0-105009880937
Journal Title
Med
Rights Holder(s)
SCOPUS
Bibliographic Citation
Med (2025)
Suggested Citation
Pasqualini R., Markosian C., Staquicini D.I., Dobroff A.S., Dodero-Rojas E., Whitford P.C., Barbu E.M., Bronk J.K., Cardó-Vila M., Christianson D.R., Dias-Neto E., Driessen W.H.P., Guzman-Rojas L., Marchiò S., Nunes D.N., de Oliveira F.S., Ozawa M.G., Proneth B., Rangel R., Smith T.L., Souza G.R., Staquicini F.I., Tang F.H.F., Baze W.B., Setubal J.C., Burns J.W., Dubick M.A., Gelovani J.G., Batchinsky A.I., Mogford J.E., Wade C.E., Holcomb J.B., Burley S.K., Onuchic J.N., Arap W. Conformational ligand-directed targeting of calcium-dependent receptors in acute trauma. Med (2025). doi:10.1016/j.medj.2025.100638 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/111221
Title
Conformational ligand-directed targeting of calcium-dependent receptors in acute trauma
Author(s)
Pasqualini R.
Markosian C.
Staquicini D.I.
Dobroff A.S.
Dodero-Rojas E.
Whitford P.C.
Barbu E.M.
Bronk J.K.
Cardó-Vila M.
Christianson D.R.
Dias-Neto E.
Driessen W.H.P.
Guzman-Rojas L.
Marchiò S.
Nunes D.N.
de Oliveira F.S.
Ozawa M.G.
Proneth B.
Rangel R.
Smith T.L.
Souza G.R.
Staquicini F.I.
Tang F.H.F.
Baze W.B.
Setubal J.C.
Burns J.W.
Dubick M.A.
Gelovani J.G.
Batchinsky A.I.
Mogford J.E.
Wade C.E.
Holcomb J.B.
Burley S.K.
Onuchic J.N.
Arap W.
Markosian C.
Staquicini D.I.
Dobroff A.S.
Dodero-Rojas E.
Whitford P.C.
Barbu E.M.
Bronk J.K.
Cardó-Vila M.
Christianson D.R.
Dias-Neto E.
Driessen W.H.P.
Guzman-Rojas L.
Marchiò S.
Nunes D.N.
de Oliveira F.S.
Ozawa M.G.
Proneth B.
Rangel R.
Smith T.L.
Souza G.R.
Staquicini F.I.
Tang F.H.F.
Baze W.B.
Setubal J.C.
Burns J.W.
Dubick M.A.
Gelovani J.G.
Batchinsky A.I.
Mogford J.E.
Wade C.E.
Holcomb J.B.
Burley S.K.
Onuchic J.N.
Arap W.
Author's Affiliation
Universidade de São Paulo
Københavns Universitet
Stanford University School of Medicine
Rutgers University–New Brunswick
The University of Texas MD Anderson Cancer Center
The University of Alabama at Birmingham
University of Texas Health Science Center at Houston
Rigshospitalet
Northeastern University
Rice University
University of Arizona College of Medicine – Tucson
Helmholtz Center Munich German Research Center for Environmental Health
Rutgers New Jersey Medical School
United Arab Emirates University
Siriraj Hospital
Università degli Studi di Torino, Scuola di Medicina
Houston Methodist
College of Engineering
Rutgers Cancer Institute of New Jersey
College of Medicine and Health Sciences United Arab Emirates University
UAB Department of Surgery
University of Arizona Cancer Center
A.C.Camargo Cancer Center
U.S. Army Institute of Surgical Research
San Diego Supercomputer Center
Defense Advanced Research Projects Agency
Michale E. Keeling Center for Comparative Medicine and Research
The Geneva Foundation
Protein Data Bank
David H. Koch Center
Københavns Universitet
Stanford University School of Medicine
Rutgers University–New Brunswick
The University of Texas MD Anderson Cancer Center
The University of Alabama at Birmingham
University of Texas Health Science Center at Houston
Rigshospitalet
Northeastern University
Rice University
University of Arizona College of Medicine – Tucson
Helmholtz Center Munich German Research Center for Environmental Health
Rutgers New Jersey Medical School
United Arab Emirates University
Siriraj Hospital
Università degli Studi di Torino, Scuola di Medicina
Houston Methodist
College of Engineering
Rutgers Cancer Institute of New Jersey
College of Medicine and Health Sciences United Arab Emirates University
UAB Department of Surgery
University of Arizona Cancer Center
A.C.Camargo Cancer Center
U.S. Army Institute of Surgical Research
San Diego Supercomputer Center
Defense Advanced Research Projects Agency
Michale E. Keeling Center for Comparative Medicine and Research
The Geneva Foundation
Protein Data Bank
David H. Koch Center
Corresponding Author(s)
Other Contributor(s)
Abstract
Background: Trauma is a leading cause of mortality, but injury-specific molecular targets remain largely unknown. We hypothesized that distinctive yet unrecognized tissue targets accessible to circulating ligands might emerge during trauma, thereby underscoring a trauma-related proteome. Methods: We screened a peptide library to discover targets in a porcine model of major trauma: compound femur fracture with hemorrhagic shock. Bioinformatics yielded conserved motifs, and candidate receptors were affinity purified. In silico and in vitro approaches served to investigate possible associations between candidate receptors and calcium, a major component of skeletal muscle and bone. In vivo homing and molecular imaging (PET/MRI and SPECT/CT) studies of the most promising ligand peptide candidate were performed in the porcine model and were also confirmed in a corresponding rat model of major trauma. Optical methodologies and molecular dynamics simulations served to explore the molecular attributes of the ligand-receptor binding. Findings: Nearly all molecular targets of the selected ligand peptides were calcium-dependent proteins, which become accessible upon trauma. We validated specific binding of homing peptides to these receptors in injured tissues, including CLRGFPALVC:CASQ1, CSEIGVRAC:HSP27, and CRQRPASGC:CALR. Notably, we determined that ligand peptide CRQRPASGC targets an injury-specific calcium-facilitated conformation of calreticulin, enabling specific molecular imaging of trauma. Conclusions: We conceptually propose the term “traumome” for the functional receptor repertoire that becomes readily amenable for ligand-directed targeting upon major trauma. These preclinical findings pave the way toward clinic-ready targeted theragnostic approaches in the setting of trauma. Funding: Major funding was provided by the Defense Advanced Research Projects Agency (DARPA).