Membrane Proteins Applications

Introduction

Because mutations and misfolding of membrane proteins have been associated with many known diseases such heart disease, cystic fibrosis, depression, obesity, cancer and many others, membrane proteins have been widely used in drug discovery in the field of medicine. Currently approximately 60% of available drugs target membrane proteins of which G protein-coupled receptors (GPCRs) and ion channels constitute the largest groups, followed by transporters and kinases. Analysis of drug targets approved by the US Food and Drug Administration (FDA) in 2016 found that GPCR and ion channels accounted for 33% and 18% of small molecule therapeutics, respectively. In this context, drugs based on GPCRs have been developed for diseases such as asthma, hypertension, rhinitis, schizophrenia, pain, migraine and prostate cancer.

Fig. 1. Representative examples of therapeutically-relevant membrane protein structures.

Applications in Practice

Membrane proteins as targets have been widely in drug discovery, and the Table 1 illustrates some specific examples ^[1].

Table.1 Examples of recent drug discovery using membrane proteins.

Target	Target type	Disease indication(s)	Therapeutic type	Discovery platform
NTS1	GPCR: neurotensin receptor	Inflammation, cancer, addiction	Small molecule	HTS fluorescence polarization assay
CCR5	GPCR: chemokine receptor	HIV	mAb	DNA immunization (chicken) boosted w/purified protein
CB1	GPCR: cannabinoid receptor	Various	mAb	Immunization (mouse hybridoma) plus phage display
CCR1	GPCR: chemokine receptor	Autoimmune diseases	mAb	Naïve library (yeast-based) screened with cells; purified protein was used for affinity maturation
AT1R	GPCR: angiotensin II receptor	Hypertension, kidney disease	mAb	Synthetic library (yeast-based) screened with purified protein
ASIC1a	Acid-sensing ion channel	Stroke	mAb	scFv phage library
P2X4	Ligand-gated ion channel	Neuropathic pain	mAb	Naïve scFv phage library
P2X3	Ligand-gated ion channel	Neuropathic pain	mAb	Immunization (mouse hybridoma)
TRPM8	Ion channel	Neuropathic pain	Small molecule	SBDD/molecular modeling using cryo-EM structures
ENT1	SLC transporter	Ischemia, pancreatic cancer	mAb	Synthetic library (ribosome display) screened with purified protein
ASCT2	SLC transporter	Tumors	Small molecule	SBDD/virtual screening using a homology model based on EAAT1 structure
APJ	GPCR: apelin receptor	Chronic heart failure	mAb	immunization (camel) with SBDD
Orexin receptors	GPCR	Insomnia	Small molecule	SBDD
MC4R	GPCR	Obesity	Small molecule	SBDD
CGRP receptor	GPCR	Migraine	Small molecule	SBDD
TREK-1	Ion channel	Depression	Small molecule	SBDD using molecular dynamics to model an intermediate conformational state based on TREK-2 structures
GLUT5	SLC transporter	Cancers	Small molecule	SBDD (virtual screening) plus liposome assay
GlyT1	SLC transporter	Nervous system disorders	mAb	Synthetic library (ribosome display) screened w/purified protein
Various K+ channels	Ion channel	Various	Small molecule	HTS of compound library
TrpV5	Ion channel	kidney diseases	Small molecule	Structure-based virtual screening
Kv1.3	Voltage-gated ion channel	Autoimmune diseases	mAb	Immunization (chicken) with proteoliposomes; screening of B cells with magnetic beads
GCGR	GPCR: glucagon receptor	Metabolic disorders	mAb	DNA immunization (llamas), phage selections with VLPs
CXCR4	GPCR: chemokine receptor	Cancer, fibrosis	mAb	Phage library of single-domain antibodies
P2X3	ligand-gated ion channel	Neuropathic pain	mAb	Immunization (chicken)
GLUT4	SLC transporter	Type 2 diabetes	mAb	Immunization (chicken)
DRD1	GPCR: dopamine receptor	Cerebral meningioma	mAb	Immunization (mouse)
Claudin-5	Structural (tight junctions)	Neurodegenerative disorders	mAb	Immunization (mouse)

Alfa Chemistry can produce high-quality native membrane protein targets and our technology maintains the structural and functional integrity of membrane protein targets, facilitating accurate discovery of drug. Meanwhile, we provide a wide range of membrane protein services such as membrane proteins solubilization and stabilization, membrane proteins purification, membrane proteins characterization, membrane proteins structural determination and so on, which will provide you with strong technical support for drug discovery. Our high-quality native, pure, stable membrane proteins are the preferred target for drug discovery scientists. Please feel free to contact us for more details.

Reference

Gulezian E., et al. Membrane protein production and formulation for drug discovery[J]. Trends in Pharmacological Sciences, 2021, 42(8): 657-674.

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