【前沿进展】屡次摘获诺贝尔奖，膜蛋白的能量超乎想象

目前全球范围内处于活跃状态的GPCRs靶向抗体大约有14个，靶点分别是CCR4、CGRPR、CCR5、GCGR、GPRC5D、GLP1R、C5AR、CB1、S1PR1、CCR8、CCR7、GPR49、AGTR1。比较有代表性的药物是Leronlimab，一种靶向CCR5的人源化IgG4单克隆抗体，是一种HIV病毒进入抑制剂。通过掩盖CCR5，阻断HIV（R5）亚型进入健康T细胞，从而保护这些细胞免受病毒感染。

靶向GPCRs药物信息（Clarivate数据库）

1. Dong HF, Wigmore K, Carrington MN, Dean M, Turpin JA, Howard OM. Variants of CCR5, which are permissive for HIV-1 infection, show distinct functional responses to CCL3, CCL4 and CCL5. Genes Immun. 2005 Oct;6(7):609-19. doi: 10.1038/sj.gene.6364247. PMID: 16015368; PMCID: PMC1369982.

2. Hanlon CD, Andrew DJ. Outside-in signaling--a brief review of GPCR signaling with a focus on the Drosophila GPCR family. J Cell Sci. 2015 Oct 1;128(19):3533-42. doi: 10.1242/jcs.175158. Epub 2015 Sep 7. PMID: 26345366; PMCID: PMC4610211.

3. Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov. 2017 Dec;16(12):829-842. doi: 10.1038/nrd.2017.178. Epub 2017 Oct 27. PMID: 29075003; PMCID: PMC6882681.

4. Wiseman DN, Otchere A, Patel JH, Uddin R, Pollock NL, Routledge SJ, Rothnie AJ, Slack C, Poyner DR, Bill RM, Goddard AD. Expression and purification of recombinant G protein-coupled receptors: A review. Protein Expr Purif. 2020 Mar;167:105524. doi: 10.1016/j.pep.2019.105524. Epub 2019 Oct 31. PMID: 31678667; PMCID: PMC6983937.

5. McLean MA, Gregory MC, Sligar SG. Nanodiscs: A Controlled Bilayer Surface for the Study of Membrane Proteins. Annu Rev Biophys. 2018 May 20;47:107-124. doi: 10.1146/annurev-biophys-070816-033620. Epub 2018 Mar 1. PMID: 29494254; PMCID: PMC6370528.

6. Ho TT, Nguyen JT, Liu J, Stanczak P, Thompson AA, Yan YG, Chen J, Allerston CK, Dillard CL, Xu H, Shoger NJ, Cameron JS, Massari ME, Aertgeerts K. Method for rapid optimization of recombinant GPCR protein expression and stability using virus-like particles. Protein Expr Purif. 2017 May;133:41-49. doi: 10.1016/j.pep.2017.03.002. Epub 2017 Mar 3. PMID: 28263854.

7. Hothersall JD, Jones AY, Dafforn TR, Perrior T, Chapman KL. Releasing the technical 'shackles' on GPCR drug discovery: opportunities enabled by detergent-free polymer lipid particle (PoLiPa) purification. Drug Discov Today. 2020 Aug 21:S1359-6446(20)30337-8. doi: 10.1016/j.drudis.2020.08.006. Epub ahead of print. PMID: 32835806.