Development and application of a high-content virion display human GPCR array

Guan-Da Syu, Shih-Chin Wang, Guangzhong Ma, Shuang Liu, Donna Pearce, Atish Prakash, Brandon Henson, Lien-Chun Weng, Devlina Ghosh, Pedro Ramos, Daniel Eichinger, Ignacio Pino, Xinzhong Dong, Jie Xiao, Shaopeng Wang, Nongjian Tao, Kwang Sik Kim (), Prashant J. Desai () and Heng Zhu ()
Additional contact information
Guan-Da Syu: Johns Hopkins University School of Medicine
Shih-Chin Wang: Johns Hopkins University School of Medicine
Guangzhong Ma: Arizona State University
Shuang Liu: Johns Hopkins University School of Medicine
Donna Pearce: Johns Hopkins University School of Medicine
Atish Prakash: Johns Hopkins University School of Medicine
Brandon Henson: Johns Hopkins University School of Medicine
Lien-Chun Weng: Johns Hopkins University School of Medicine
Devlina Ghosh: Johns Hopkins University School of Medicine
Pedro Ramos: CDI Laboratories, Inc.
Daniel Eichinger: CDI Laboratories, Inc.
Ignacio Pino: CDI Laboratories, Inc.
Xinzhong Dong: Johns Hopkins University School of Medicine
Jie Xiao: Johns Hopkins University School of Medicine
Shaopeng Wang: Arizona State University
Nongjian Tao: Arizona State University
Kwang Sik Kim: Johns Hopkins University School of Medicine
Prashant J. Desai: Johns Hopkins University School of Medicine
Heng Zhu: Johns Hopkins University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Human G protein-coupled receptors (GPCRs) respond to various ligands and stimuli. However, GPCRs rely on membrane for proper folding, making their biochemical properties difficult to study. By displaying GPCRs in viral envelopes, we fabricated a Virion Display (VirD) array containing 315 non-olfactory human GPCRs for functional characterization. Using this array, we found that 10 of 20 anti-GPCR mAbs were ultra-specific. We further demonstrated that those failed in the mAb assays could recognize their canonical ligands, suggesting proper folding. Next, using two peptide ligands on the VirD-GPCR array, we identified expected interactions and novel interactions. Finally, we screened the array with group B Streptococcus, a major cause of neonatal meningitis, and demonstrated that inhibition of a newly identified target, CysLTR1, reduced bacterial penetration both in vitro and in vivo. We believe that the VirD-GPCR array holds great potential for high-throughput screening for small molecule drugs, affinity reagents, and ligand deorphanization.

Date: 2019
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DOI: 10.1038/s41467-019-09938-9

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