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Preprint
The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS
bioRxiv
11 Jul 2025
PMID: 40672153
Abstract
G-protein coupled receptors (GPCRs) are transmembrane proteins that mediate a range of signaling functions and, therefore, offer targets for a number of therapeutic interventions. Chemokine receptor CXCR4, a GPCR, plays versatile roles in normal and abnormal physiological processes. Synthetic CXCR4 antagonists have been extensively studied and approved for the clinical treatment of cancer and other diseases. We recently elucidated the structural mechanisms underlying CXCR4 antagonism using cryogenic electron microscopy (cryo-EM). CXCR4 agonism by synthetic molecules is an unanticipated therapeutic intervention we recently unveiled. The structural mechanisms underlying those actions remain poorly understood yet could help elucidate a new class of drugs. Here we demonstrate a synthetic dual-moiety strategy that combines simplified agonistic and antagonistic moieties taken from natural agonistic and antagonistic chemokines, respectively, to design de novo peptide mimics of biological function of natural CXCR4 agonist SDF-1α. Two peptides so generated, SDV1a and SDVX1 were shown to mimic the action of SDF-1α in activating CXCR4 signaling pathways and cell migration. The structural mechanism of these peptides in the mimicry of CXCR4 agonism was illustrated by cryo-EM structures of CXCR4 bound and activated by the peptides in the presence of G protein, revealing common interactions with the receptor by these peptides in comparison with SDF-1α that explain their close mimicry and conformational changes leading to CXCR4 signal activation. The therapeutic benefit of one of these peptides, SDV1a, was demonstrated in the SOD1G93A mouse model of the spinal motor neuron degenerative disease, amyotrophic lateral sclerosis (ALS) wherein the success of neuroprotective actions of transplanted human neural stem cells (hNSCs) is directly correlated with the expanse of diseased neuroaxis traversed by the donor cells; SDV1a enabled broader neuroprotective coverage while also permitting a much less invasive route of cell administration for extending life. Taken together, these results provide insights into the structural determinants of therapeutic CXCR4 agonism which may allow the design of adjunctive drugs that improve cell-based treatments of central nervous system (CNS) diseases.
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Details
- Title
- The cryo-EM-delineated mechanism underlying mimicry of CXCR4 agonism enables widespread stem cell neuroprotection in a mouse model of ALS
- Creators
- Xiaohong Sang - Chinese University of Hong Kong, ShenzhenHaizhan Jiao - Chinese University of Hong Kong, ShenzhenQian Meng - Tsinghua UniversityXiong Fang - Tsinghua UniversityKartik S. Sundaram - Sanford Burnham Prebys Medical Discovery InstituteJiao Zhou - Chinese University of Hong Kong, ShenzhenYan Xu - University of California, San DiegoAsuka I. W. Alvarado - Sanford Burnham Prebys Medical Discovery InstituteRuslan L. Nuryyev - Sanford Burnham Prebys Medical Discovery InstituteJitka Ourenik - Sanford Burnham Prebys Medical Discovery InstituteVaclav Ourednik - Sanford Burnham Prebys Medical Discovery InstituteIris S. Huang - Sanford Burnham Prebys Medical Discovery InstituteXiang Liu - Guangdong Pharmaceutical UniversityYuheng Mei - Chinese University of Hong Kong, ShenzhenTingli Qian - Chinese University of Hong Kong, ShenzhenAaron Ciechanover - Technion – Israel Institute of TechnologyDonald P. Pizzo - University of California, San DiegoMichael A. Lane - Drexel UniversityLyandysha V. Zholudeva - Gladstone InstitutesJing An - University of California, San DiegoEvan Y. Snyder - Sanford Burnham Prebys Medical Discovery InstituteHongli Hu - Chinese University of Hong Kong, ShenzhenZiwei Huang - University of California, San Diego
- Publication Details
- bioRxiv
- Publisher
- Cold Spring Harbor Laboratory
- Edition
- 1.1
- Resource Type
- Preprint
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Other Identifier
- 991022064895104721