Cyclosporin A-Based PROTACs Can Deplete Abundant Cellular Cyclophilin A without Suppressing T Cell Activation DOI Creative Commons

Katharina Hilbig,

Russell Towers,

Marc Schmitz

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(12), P. 2779 - 2779

Published: June 11, 2024

Cyclophilin A (CypA), the cellular receptor of immunosuppressant cyclosporin (CsA), is an abundant cytosolic protein and involved in a variety diseases. For example, CypA supports cancer proliferation mediates viral infections, such as human immunodeficiency virus 1 (HIV-1). Here, we present design PROTAC (proteolysis targeting chimera) compounds against to induce its intracellular proteolysis investigate their effect on immune cells. Interestingly, upon connecting E3 ligase ligands, both peptide-based low-affinity binders CsA-based high-affinity can degrade at nM concentration HeLa cells fibroblast As immunosuppressive CsA not directly associated with binding but inhibition phosphatase calcineurin by CypA:CsA complex, investigated whether compound could degradation without affecting activation P3, most efficient discovered from this study, deplete lymphocytes cell cytokine production. This work demonstrates feasibility approach depleting low drug dosage cells, allowing us potential therapeutic effects endogenous future.

Language: Английский

Targeted protein degradation: advances in drug discovery and clinical practice DOI Creative Commons
Guangcai Zhong, Xiaoyu Chang, Weilin Xie

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

Citations

22
The extracellular cyclophilin A-integrin β2 complex as a therapeutic target of viral pneumonia DOI Creative Commons

Xiaoyuan Bai,

Wenxian Yang,

Yuna Zhao

et al.

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(5), P. 1510 - 1525

Published: March 7, 2024

The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed cytoplasm resting cells released into extracellular space response to stimuli. Extracellular CypA (eCypA) upregulated promotes severe COVID-19 patients. However, how eCypA virus-induced remains elusive. Here, we observe that induced by influenza B viruses SARS-CoV-2 cells, mice, or Anti-CypA mAb reduces pro-inflammatory cytokines production, leukocytes infiltration, lung injury virus-infected mice. Mechanistically, binding integrin β2 triggers activation, thereby facilitating leukocyte trafficking production via focal adhesion kinase (FAK)/GTPase FAK/ERK/P65 pathways, respectively. These functions suppressed anti-CypA specifically blocks eCypA-integrin interaction. Overall, our findings reveal signaling mediates response, indicating a potential target for antibody therapy against pneumonia.

Language: Английский

Citations

4
Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV DOI Creative Commons
Lydia S. Newton, Clara Gathmann, Sophie Ridewood

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 10, 2025

Language: Английский

Citations

0
Synergizing Proteolysis-Targeting Chimeras and Nanoscale Exosome-Based Delivery Mechanisms for HIV and Antiviral Therapeutics DOI
Nobendu Mukerjee, Swastika Maitra, Arabinda Ghosh

et al.

ACS Applied Nano Materials, Journal Year: 2024, Volume and Issue: 7(4), P. 3499 - 3514

Published: Feb. 8, 2024

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 resistance nonspecific actions, this paper unveils transformative approach. We introduce an innovative synergy between proteolysis-targeting chimeras (PROTACs) exosome-based delivery mechanisms, heralding era in combating HIV similar diseases. PROTACs emerge trailblazing solution, strategically targeting decomposing crucial proteins, thus, obstructing replication diminishing pathogenesis. Complementing this, use systems─nature's own nanoscale couriers─ensures precise effective transportation these dynamic directly to infected cells reservoirs. This synergistic strategy is not just leap forward therapy; it represents paradigm shift interventions large. path realizing full potential avant-garde technologies lies sustained research investments, cross-disciplinary collaborations, rigorous safety efficacy trials. By channeling efforts toward HIV, cornerstone health research, we are envisioning but actively forging path-breaking advancements therapeutics. more than scientific progress; beacon hope, promising significantly uplift lives those battling formidable

Language: Английский

Citations

3
Recent advances in PROTAC-based antiviral and antibacterial therapeutics DOI
Can Zhou, Shiwei Yang, Jun Wang

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108437 - 108437

Published: April 1, 2025

Language: Английский

Citations

0
The binding of extracellular cyclophilin A to ACE2 and CD147 triggers psoriasis-like inflammation DOI Creative Commons
Wenxian Yang,

Xiaoyuan Bai,

Xiaoxiao Jia

et al.

Journal of Autoimmunity, Journal Year: 2024, Volume and Issue: 148, P. 103293 - 103293

Published: Aug. 2, 2024

Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with cytokine production. Cyclophilin A (CypA) an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased the lesion serum of patients psoriasis, which positively correlated area severity index. Furthermore, extracellular (eCypA) triggered psoriasis-like responses keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, expression imiquimod-induced mice. Notably, therapeutic effect was better than clinically used anti-IL-17A methotrexate. Mechanistically, eCypA binds to ACE2 CD147 blocked by mAb. not only induces dimerization phosphorylation trigger JAK1/STAT3 signaling pathway for but also interacts promote PI3K/AKT/mTOR signaling-mediated proliferation. These findings demonstrate binding cooperatively triggers inflammation promising candidate treatment psoriasis.

Language: Английский

Citations

1
Targeted degrader technologies as prospective SARS-CoV-2 therapies DOI
Rabia Khurshid, Joseph M. Schulz, Jiaming Hu

et al.

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 29(1), P. 103847 - 103847

Published: Nov. 28, 2023

Language: Английский

Citations

3
Cyclophilin A facilitates influenza B virus replication by stabilizing viral proteins DOI Creative Commons
Huizi Li, Wenhui Fan, Jie Min

et al.

iScience, Journal Year: 2023, Volume and Issue: 26(12), P. 108515 - 108515

Published: Nov. 23, 2023

Influenza B circulates annually and causes substantial disease burden in humans. However, little is known about the infection mechanisms of influenza virus (IBV). Here, we find that host factor cyclophilin A (CypA) facilitates IBV replication by targeting non-structural protein 1 (BNS1) nucleoprotein (BNP). CypA promotes OTUD4-mediated K48-linked BNS1 deubiquitination to stabilize upregulating OTUD4 expression. Meanwhile, E3 ligase MIB1 competitively interact with BNP inhibit its proteasomal degradation. Moreover, cyclosporine treatment or R55A mutation results an impaired function replication. Notably, hijacks into nucleus enhance activity viral ribonucleoprotein complexes enhancing interaction between polymerase basic 1. Taken together, this study unveils critical role facilitating replication, suggesting a promising target for anti-IBV drug.

Language: Английский

Citations

2
Cyclosporin A-Based PROTACs Can Deplete Abundant Cellular Cyclophilin A without Suppressing T Cell Activation DOI Creative Commons

Katharina Hilbig,

Russell Towers,

Marc Schmitz

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(12), P. 2779 - 2779

Published: June 11, 2024

Cyclophilin A (CypA), the cellular receptor of immunosuppressant cyclosporin (CsA), is an abundant cytosolic protein and involved in a variety diseases. For example, CypA supports cancer proliferation mediates viral infections, such as human immunodeficiency virus 1 (HIV-1). Here, we present design PROTAC (proteolysis targeting chimera) compounds against to induce its intracellular proteolysis investigate their effect on immune cells. Interestingly, upon connecting E3 ligase ligands, both peptide-based low-affinity binders CsA-based high-affinity can degrade at nM concentration HeLa cells fibroblast As immunosuppressive CsA not directly associated with binding but inhibition phosphatase calcineurin by CypA:CsA complex, investigated whether compound could degradation without affecting activation P3, most efficient discovered from this study, deplete lymphocytes cell cytokine production. This work demonstrates feasibility approach depleting low drug dosage cells, allowing us potential therapeutic effects endogenous future.

Language: Английский

Citations

0