# Extracellular and Membrane Protein: Structure, Biological Functions, Diseases, and an Emerging Modality for Drug Discovery

## TL;DR

This review discusses how targeting and degrading faulty extracellular and membrane proteins can lead to new treatments for diseases like cancer and neurodegeneration.

## Contribution

The paper introduces emerging strategies for targeted protein degradation, including cell-surface receptor-based and nanoparticle-based approaches.

## Key findings

- Targeted protein degradation (TPD) can completely remove faulty proteins, unlike traditional drugs that only block active sites.
- New TPD strategies include using cell-surface receptors, lysosomal tools, E3 ligases, and nanoparticles.
- Future directions include combining degraders with antibodies and using tissue-specific receptors for better disease targeting.

## Abstract

Extracellular and membrane proteins serve important roles. They manage cellular communication, structure support, and immune defense. When they malfunction, it cause many diseases like cancer, neurodegeneration, and cardiovascular disorders. Targeted protein degradation (TPD) is a promising therapeutic strategy and aims to remove these faulty proteins. This approach goes beyond traditional drugs, which only block the active site of proteins. The aim of TPD is to entirely remove the targeted proteins in cells. This review began with explaining the structure and functions of extracellular and membrane proteins, highlighting their connection with disease. It then went on to discuss new strategies for their degradation. These emerging strategies include those that take advantage of cell‐surface receptors to target lysosomes, intracellular lysosomal sorting tools, E3 ligases, and nanoparticle‐based systems. A comparison of different TPD tools was also provided. Discussion compared strengths and weaknesses of approaches with small molecules, antibodies, nanobodies, and aptamers. Finally, the review outlined future directions for advanced TPD strategies. Next steps would be the combination of degraders with therapeutic antibodies. Another research interest is the utilization of tissue‐specific receptors from genetic databases. Moreover, the application of TPD to immune and neurodegenerative diseases is also a critical goal for the future.

Targeted protein degradation represents a paradigm shift from traditional protein inhibition to complete protein elimination. This is achieved through three main strategies for degrading extracellular and membrane proteins: recruitment of cell‐surface LTRs, engagement of intracellular proteins, and receptor‐independent mechanisms.