PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

Sincere, Nuwayo Ishimwe; Anand, Krishnan; Ashique, Sumel; Yang, Jing; You, Chongge

doi:10.3390/molecules28104014

Cited by 22 publications

(10 citation statements)

References 139 publications

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“…In comparative ternary complex methodologies, an intermediate state (e.g., binary) of high specificity is typically required to drive a pathway with high-level activity. In many cases, the lack of clinical translation of some targeted systems 204 may be a consequence of missing underlying analyses associated with details of kinetic (e.g., k on and k off ) parameters. Such analyses would similarly underpin the broader fields of substrate-, ligand-, and proximity-directed methods.…”

Section: Affinity Proteolysis: a Prominent Case Of Biomolecule-direct...mentioning

confidence: 99%

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Late-Stage Functionalization of Living Organisms: Rethinking Selectivity in Biology

Giltrap,

Yuan,

Davis

2024

Chem. Rev.

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With unlimited selectivity, full post-translational chemical control of biology would circumvent the dogma of genetic control. The resulting direct manipulation of organisms would enable atomic-level precision in “editing” of function. We argue that a key aspect that is still missing in our ability to do this (at least with a high degree of control) is the selectivity of a given chemical reaction in a living organism. In this Review, we systematize existing illustrative examples of chemical selectivity, as well as identify needed chemical selectivities set in a hierarchy of anatomical complexity: organismo- (selectivity for a given organism over another), tissuo- (selectivity for a given tissue type in a living organism), cellulo- (selectivity for a given cell type in an organism or tissue), and organelloselectivity (selectivity for a given organelle or discrete body within a cell). Finally, we analyze more traditional concepts such as regio-, chemo-, and stereoselective reactions where additionally appropriate. This survey of late-stage biomolecule methods emphasizes, where possible, functional consequences (i.e., biological function). In this way, we explore a concept of late-stage functionalization of living organisms (where “late” is taken to mean at a given state of an organism in time) in which programmed and selective chemical reactions take place in life. By building on precisely analyzed notions (e.g., mechanism and selectivity) we believe that the logic of chemical methodology might ultimately be applied to increasingly complex molecular constructs in biology. This could allow principles developed at the simple, small-molecule level to progress hierarchically even to manipulation of physiology.

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Section: Affinity Proteolysis: a Prominent Case Of Biomolecule-direct...mentioning

confidence: 99%

“…, binary) of high specificity is typically required to drive a pathway with high-level activity. In many cases, the lack of clinical translation of some targeted systems may be a consequence of missing underlying analyses associated with details of kinetic ( e.g. , k on and k off ) parameters.…”

Section: Biomolecule (Substrate) Selectivitymentioning

confidence: 99%

Late-Stage Functionalization of Living Organisms: Rethinking Selectivity in Biology

Giltrap,

Yuan,

Davis

2024

Chem. Rev.

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“…The linker, meanwhile, serves as a bridge between the two ligands. Its design, in terms of length and flexibility, is essential to ensure that the target protein and the E3 ligase can be brought into close proximity, thereby facilitating the transfer of ubiquitin to the target protein. − ,, Thus, the production of PROTACs is an intricate process of molecular design and synthesis.…”

Section: Biogenesis Of Exosomes and Protacs: A Detailed Examination O...mentioning

confidence: 99%

Synergizing Proteolysis-Targeting Chimeras and Nanoscale Exosome-Based Delivery Mechanisms for HIV and Antiviral Therapeutics

Mukerjee,

Maitra,

Ghosh

et al. 2024

ACS Appl. Nano Mater.

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The global fight against Human Immunodeficiency Virus (HIV) and related viral infections stands at a pivotal juncture, demanding groundbreaking therapeutic strategies. Facing the challenges of existing antiviral treatments, such as viral resistance and nonspecific actions, this paper unveils a transformative approach. We introduce an innovative synergy between proteolysis-targeting chimeras (PROTACs) and exosome-based delivery mechanisms, heralding an innovative era in combating HIV and similar viral diseases. PROTACs emerge as a trailblazing solution, strategically targeting and decomposing crucial viral proteins, and thus, obstructing viral replication and diminishing pathogenesis. Complementing this, the use of exosome-based delivery systemsnature’s own nanoscale couriersensures the precise and effective transportation of these dynamic chimeras directly to infected cells and viral reservoirs. This synergistic strategy is not just a leap forward in HIV therapy; it represents a paradigm shift in antiviral interventions at large. The path to realizing the full potential of these avant-garde technologies lies in sustained research investments, cross-disciplinary collaborations, and rigorous safety and efficacy trials. By channeling these efforts toward HIV, a cornerstone in global health research, we are not just envisioning but actively forging path-breaking advancements in antiviral therapeutics. This represents more than scientific progress; it is a beacon of hope, promising to significantly uplift the lives of those battling these formidable diseases.

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“…The linker connects the target protein ligand and the E3 ligase ligand ( Figure 1 ). The length and composition of the linker are crucial for the effective proximity of the target protein and the E3 ligase, facilitating the transfer of ubiquitin from the E3 ligase to the target protein ( 62 , 63 ).…”

Section: Protacsmentioning

confidence: 99%

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Ren,

Wang,

Liu

et al. 2024

Front. Immunol.

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Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

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PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies

Cited by 22 publications

References 139 publications

Late-Stage Functionalization of Living Organisms: Rethinking Selectivity in Biology

Late-Stage Functionalization of Living Organisms: Rethinking Selectivity in Biology

Synergizing Proteolysis-Targeting Chimeras and Nanoscale Exosome-Based Delivery Mechanisms for HIV and Antiviral Therapeutics

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

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