Targeted protein degradation in the transmembrane and extracellular space.
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| Title: | Targeted protein degradation in the transmembrane and extracellular space. |
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| Authors: | Zhu, Rongfeng (AUTHOR), Zhang, Heng (AUTHOR), Chen, Peng R. (AUTHOR) |
| Source: | Science. 11/27/2025, Vol. 390 Issue 6776, p1-11. 11p. |
| Subjects: | Membrane proteins, Therapeutics, Biological research methodology, Treatment effectiveness, Extracellular matrix proteins, Proteolysis, Endocytosis, Cell physiology |
| Abstract: | Transmembrane and extracellular proteins play crucial roles in diverse cellular functions and communication, affecting the progression and treatment of various diseases by mediating vital cellular processes. Whereas targeted protein degradation (TPD) represents an advancing therapeutic modality that leverages cellular degradation machinery to eliminate proteins of interest, present strategies have been largely confined to intracellular targets. Now, emerging strategies toward transmembrane and extracellular proteins are rapidly expanding the horizon of this powerful technology. Here, we review TPD in the transmembrane and extracellular space (meTPD) and discuss platform technologies, features, applications, and limitations. We focus on the conceptual innovations used in developing the present meTPD technology as well as its potential value for biological research and therapeutic interventions. Editor's summary: Targeted protein degradation is a therapeutic strategy that entails hijacking a cell's natural pathways for marking proteins for elimination. Intracellular proteins can often be targeted to the proteasome by small molecules that work by bringing target proteins together in space with E3 ubiquitin ligases. However, extracellular and transmembrane targets, which generally need to be targeted on the outside surface of the cell, present a different set of challenges and opportunities. Zhu et al. reviewed recent advances that expand the range or targets, drug modalities, and control mechanisms, enabling promising therapeutic applications. —Michael A. Funk BACKGROUND: Transmembrane and extracellular proteins play critical roles in maintaining cellular functions and communication, tissue integrity, and overall homeostasis of the body, and their dysfunction is known to cause cancer, neurodegeneration, inflammation, autoimmune diseases, and metabolic disorders. Direct manipulation of membrane proteins often requires the binding of a drug to the target's functional site to modulate its activity. Although targeted protein degradation (TPD) strategies have rapidly emerged as paradigm-shifting technologies to selectively degrade the target protein without necessarily targeting the functional site, classic TPD strategies such as proteolysis-targeting chimeras (PROTACs) and molecular glues are predominantly confined to targeting intracellular proteins owing to the localization of the cellular protein quality-control machinery. Recently, several approaches have emerged as a general strategy for TPD in the transmembrane and extracellular space (meTPD). We review advances in meTPD, including their distinctive features, challenges, and opportunities, as well as their applications in biology, ranging from basic advances to the development of cellular and molecular therapeutics. ADVANCES: Since the emergence of the first meTPD strategy in late 2020, more than 30 distinct meTPD concepts have been developed, with large variance in their modalities and mechanisms. meTPD demonstrates notable efficacy, exceeding 70% in many cases and beyond 95% after optimization. The fundamental mechanistic distinction between meTPD and classic intracellular TPD is that the former needs to direct the target protein to enter the cell from the cell surface or extracellular space. Rather than a simple or natural extension of intracellular TPD, meTPD represents the integration of TPD and intracellular protein delivery. We highlight key concepts and developments, including the development of meTPD degraders that undergo rapid endocytosis, as well as unmet needs and several emerging directions that hold promise for advancing the meTPD field, including covalent, multispecific, and conditionally activatable meTPD strategies. OUTLOOK: meTPD holds great potential for biological research through rapid, convenient, and reversible membrane protein degradation, avoiding the issue of compensation and variation in genetic backgrounds. Furthermore, although meTPD development is in the early stages, several strategies have led to the founding of biotech companies, highlighting the rapidly growing interest in the pharmaceutical industry as well as the therapeutic potential of meTPD. For example, the meTPD chimera BHV-1300 has entered a phase 1 clinical trial; in preclinical studies as a treatment for myasthenia gravis, it exhibited faster immunoglobulin G (IgG) reduction with intermittent dosing than the mainstream FcRn inhibitors. Because meTPD degraders undergo internalization and endocytosis to achieve target degradation, they also offer a platform for intracellular delivery of various cargoes, such as toxins, signaling modulators, and antigen peptides. As an example, the combination of meTPD and small interfering RNA has facilitated simultaneous target degradation and gene silencing. We anticipate that meTPD-based drug and tracer delivery and vaccine generation will have far-reaching clinical impact. meTPD strategies.: meTPD triggers target internalization and subsequent degradation, representing the integration of TPD with intracellular delivery. Beyond the degradation of a single target, emerging concepts in meTPD hold promise for expansion of the meTPD functional repertoire. Development of meTPD also offers broad applications in medical research. CNS, central nervous system; GPCRs, G protein–coupled receptors; POI, protein of interest; TME, tumor microenvironment. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Transmembrane and extracellular proteins play crucial roles in diverse cellular functions and communication, affecting the progression and treatment of various diseases by mediating vital cellular processes. Whereas targeted protein degradation (TPD) represents an advancing therapeutic modality that leverages cellular degradation machinery to eliminate proteins of interest, present strategies have been largely confined to intracellular targets. Now, emerging strategies toward transmembrane and extracellular proteins are rapidly expanding the horizon of this powerful technology. Here, we review TPD in the transmembrane and extracellular space (meTPD) and discuss platform technologies, features, applications, and limitations. We focus on the conceptual innovations used in developing the present meTPD technology as well as its potential value for biological research and therapeutic interventions. Editor's summary: Targeted protein degradation is a therapeutic strategy that entails hijacking a cell's natural pathways for marking proteins for elimination. Intracellular proteins can often be targeted to the proteasome by small molecules that work by bringing target proteins together in space with E3 ubiquitin ligases. However, extracellular and transmembrane targets, which generally need to be targeted on the outside surface of the cell, present a different set of challenges and opportunities. Zhu et al. reviewed recent advances that expand the range or targets, drug modalities, and control mechanisms, enabling promising therapeutic applications. —Michael A. Funk BACKGROUND: Transmembrane and extracellular proteins play critical roles in maintaining cellular functions and communication, tissue integrity, and overall homeostasis of the body, and their dysfunction is known to cause cancer, neurodegeneration, inflammation, autoimmune diseases, and metabolic disorders. Direct manipulation of membrane proteins often requires the binding of a drug to the target's functional site to modulate its activity. Although targeted protein degradation (TPD) strategies have rapidly emerged as paradigm-shifting technologies to selectively degrade the target protein without necessarily targeting the functional site, classic TPD strategies such as proteolysis-targeting chimeras (PROTACs) and molecular glues are predominantly confined to targeting intracellular proteins owing to the localization of the cellular protein quality-control machinery. Recently, several approaches have emerged as a general strategy for TPD in the transmembrane and extracellular space (meTPD). We review advances in meTPD, including their distinctive features, challenges, and opportunities, as well as their applications in biology, ranging from basic advances to the development of cellular and molecular therapeutics. ADVANCES: Since the emergence of the first meTPD strategy in late 2020, more than 30 distinct meTPD concepts have been developed, with large variance in their modalities and mechanisms. meTPD demonstrates notable efficacy, exceeding 70% in many cases and beyond 95% after optimization. The fundamental mechanistic distinction between meTPD and classic intracellular TPD is that the former needs to direct the target protein to enter the cell from the cell surface or extracellular space. Rather than a simple or natural extension of intracellular TPD, meTPD represents the integration of TPD and intracellular protein delivery. We highlight key concepts and developments, including the development of meTPD degraders that undergo rapid endocytosis, as well as unmet needs and several emerging directions that hold promise for advancing the meTPD field, including covalent, multispecific, and conditionally activatable meTPD strategies. OUTLOOK: meTPD holds great potential for biological research through rapid, convenient, and reversible membrane protein degradation, avoiding the issue of compensation and variation in genetic backgrounds. Furthermore, although meTPD development is in the early stages, several strategies have led to the founding of biotech companies, highlighting the rapidly growing interest in the pharmaceutical industry as well as the therapeutic potential of meTPD. For example, the meTPD chimera BHV-1300 has entered a phase 1 clinical trial; in preclinical studies as a treatment for myasthenia gravis, it exhibited faster immunoglobulin G (IgG) reduction with intermittent dosing than the mainstream FcRn inhibitors. Because meTPD degraders undergo internalization and endocytosis to achieve target degradation, they also offer a platform for intracellular delivery of various cargoes, such as toxins, signaling modulators, and antigen peptides. As an example, the combination of meTPD and small interfering RNA has facilitated simultaneous target degradation and gene silencing. We anticipate that meTPD-based drug and tracer delivery and vaccine generation will have far-reaching clinical impact. meTPD strategies.: meTPD triggers target internalization and subsequent degradation, representing the integration of TPD with intracellular delivery. Beyond the degradation of a single target, emerging concepts in meTPD hold promise for expansion of the meTPD functional repertoire. Development of meTPD also offers broad applications in medical research. CNS, central nervous system; GPCRs, G protein–coupled receptors; POI, protein of interest; TME, tumor microenvironment. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adx5094 |
