A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates Ex Vivo Reservoirs DOI Open Access
L.‐H. Chang, Michael T. Yin, Gregory M. Laird

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 17, 2024

ABSTRACT The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) selectively inducing cell death infected cells. However, current LRAs have shown limited efficacy eliminating the ex vivo HIV reservoir. We repurposed PZ703b, pro-apoptotic protein degrader initially developed for anti-leukemia therapy, target eradication. PZ703b induced degradation Bcl-2 Bcl-xL, activating non-canonical NF-kB pathway caspases cascade, resulting reversal selective apoptosis Treatment from ART-suppressed patients achieved ∼50% reduction replication-competent Our study provides proof-of-concept using degraders reverse induce death, highlighting PZ703b’s potential cure strategies. This approach may pave way novel therapeutic interventions aimed at HIV-inducible

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
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

1
Antiviral strategies against influenza virus: an update on approved and innovative therapeutic approaches DOI Creative Commons
Anna Bonomini, Beatrice Mercorelli, Arianna Loregian

et al.

Cellular and Molecular Life Sciences, Journal Year: 2025, Volume and Issue: 82(1)

Published: Feb. 13, 2025

Language: Английский

Citations

0
VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation DOI
Kyle Mangano, Robert G. Guenette,

Spencer Hill

et al.

Cell chemical biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Minimizes Ex Vivo Reservoirs from Patients DOI Open Access
L.‐H. Chang, Michael T. Yin, Gregory M. Laird

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2772 - 2772

Published: March 19, 2025

The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) selectively inducing cell death infected cells. However, current LRAs have shown limited efficacy eliminating the ex vivo HIV reservoir thus failed clinical study. In this study, we repurposed PZ703b, pro-apoptotic protein degrader initially developed for anti-leukemia therapy, target eradication. PZ703b induced degradation Bcl-2 Bcl-xL, activating non-canonical NF-kB pathway caspases cascade, resulting reversal selective apoptosis treatment from ART-suppressed patients led approximately 50% reduction replication-competent reservoir. While result does not reach threshold required complete cure, it demonstrates potential dual Bcl-2/Bcl-xL death. Our study provides proof-of-concept using degraders as novel category therapeutic strategies aimed at reducing reservoirs. This approach may pave way further exploration targeted interventions eliminate HIV-inducible

Language: Английский

Citations

0
Targeted protein degraders of SARS-CoV-2 Mpro are more active than enzymatic inhibition alone with activity against nirmatrelvir resistant virus DOI Creative Commons
Baolong Pan, Simon J. Mountford, Maki Kiso

et al.

Communications Medicine, Journal Year: 2025, Volume and Issue: 5(1)

Published: April 26, 2025

Effective antiviral therapy is lacking for most viral infections, and when available, frequently compromised by the selection of resistance. Targeted protein degraders could provide an avenue to more effective antivirals, able overcome The aim this study was determine whether adaptation SARS-CoV-2 main protease (Mpro, also described as chymotrypsin-like (3CLpro) or non-structural 5 (Nsp5)) inhibitors into leads increased activity, including activity against resistant virus. We adapted clinically approved Mpro inhibitor nirmatrelvir a panel degraders. Size-matched non-degrading controls were synthesised discriminate degradation from inhibition activity. Degrader confirmed using inducible Mpro-HiBiT tag expressing cell line. Antiviral both wildtype nirmatrelvir-resistant virus performed infection susceptible lines. Here we show three compounds, derived utilising VHL IAP ubiquitin ligase recruiters, capable degrading in concentration, time proteasome dependent fashion. These compounds degrade mutant Mpro. potent these possesses enhanced multiple strains compared controls. This work demonstrates feasibility generating inhibitors, confirms that possess higher potency virus, size matched enzymatic inhibitors. findings further support development targeted drugs, which may lead therapies future.

Language: Английский

Citations

0
MHC-I pathway disruption by viruses: insights into immune evasion and vaccine design for animals DOI Creative Commons
Yanan Wu,

Zhuoya Sun,

Lu Xia

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: May 8, 2025

Among various pathogens, viruses pose significant threats to the livestock and poultry industry, resulting in substantial annual costs due production losses vaccination. The MHC-I presentation pathway is a crucial surveillance mechanism for preventing viral infections. Consequently, many have evolved sophisticated strategies inhibit of peptides by CD8 + T-cells, thereby evading immune system. Understanding mechanisms that suppress identifying specific binding are essential comprehending evasion developing effective animal vaccines. This review summarizes recognition, including inhibition molecules synthesis, degradation, transport, assembly, which affect surface expression during We also present evidence frequently lost numerous infections offer new insights into underlying through inactivate antigen pathway. Collectively, these advanced findings on from could inform development more effectives restore immunological control over improve vaccines industry.

Language: Английский

Citations

0
PROTAC Technology as a New Tool for Modern Pharmacotherapy DOI Creative Commons

Natalia Kubryń,

Łukasz Fijałkowski, Jacek Nowaczyk

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(10), P. 2123 - 2123

Published: May 11, 2025

The publication focuses on the innovative applications of PROTAC (proteolysis-targeting chimera) technology in modern pharmacotherapy, with particular emphasis cancer treatment. PROTACs represent an advanced therapeutic strategy that enables selective protein degradation, opening new possibilities drug design. This shows potential treatment cancers, viral infections (such as HIV and COVID-19), chronic diseases including atherosclerosis, Alzheimer’s disease, atopic dermatitis, Huntington’s disease. Promising results from clinical studies compound ARV-471 confirm effectiveness this approach. New types PROTACs, like TF-PROTAC PhosphoTAC, are designed to enhance effectiveness, stability, absorption drugs. conclusions review highlight broad various their relevance for future therapies, particularly oncology.

Language: Английский

Citations

0
COVID-19: the renaissance of science in the face of adversity DOI Creative Commons
Luca Perico, Giuseppe Remuzzi

Frontiers in Science, Journal Year: 2024, Volume and Issue: 2

Published: May 23, 2024

Keywords: COVID-19, SARS-CoV-2, epidemic models, mRNA vaccines, vaccinology, data science, digital medicine, artificial intelligence

Language: Английский

Citations

0
VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation DOI Creative Commons
Kyle Mangano,

Robert G. Guenette,

Spencer Hill

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 16, 2024

ABSTRACT In targeted protein degradation (TPD) a of interest is degraded by chemically induced proximity to an E3 ubiquitin ligase. One limitation using TPD therapeutically that most ligases have broad tissue expression, which can contribute toxicity via target in healthy cells. Many pathogenic and oncogenic viruses encode (vE3s), de facto strictly limited expression diseased Here, we provide proof-of-concept for Vi ral P an- E ssential R emoving Ta rgeting C himeras (VIPER-TACs) are bi-functional molecules utilize viral selectively degrade pan-essential proteins eliminate We find the human papillomavirus (HPV) ligase E6 SARS1 model HPV-positive cervical cancer kill expressing Thus, VIPER-TACs capacity dramatically increase therapeutic window, alleviate concerns, ultimately expand potential space TPD.

Language: Английский

Citations

0