Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents

Han, Jinhe; Lee, Myoung Kyu; Jang, Yejin; Cho, Won‐Jea; Kim, Meeheyin

doi:10.1016/j.drudis.2022.05.016

Cited by 16 publications

(16 citation statements)

References 160 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of these inhibitors, cyclosporin A, has been used in the clinic as an immunosuppressant during organ transplantation for decades. Due to the recent confirmation of the importance of the mitochondrial permeability transition pore in the development of many diseases, inhibitors such as cyclosporine A have now been proposed as possible treatment options for these conditions, including viral infections (Winquist & Gribkoff, 2020; Han et al , 2022).…”

Section: Discussionmentioning

confidence: 99%

Lipin‐2 regulates the antiviral and anti‐inflammatory responses to interferon

de Pablo,

Meana,

Martínez‐García

et al. 2023

EMBO Reports

View full text Add to dashboard Cite

Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin‐2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT‐1‐dependent manner. Lipin‐2 inhibits viral replication both in vitro and in vivo. Moreover, lipin‐2 also acts as a regulator of inflammation in a viral context by reducing the signaling through TLR3 and the generation of ROS and release of mtDNA that ultimately activate the NLRP3 inflammasome. Inhibitors of mtDNA release from mitochondria restrict IL‐1β production in lipin‐2‐deficient animals in a model of viral infection. Finally, analyses of databases from COVID‐19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease. Overall, these results uncover novel regulatory mechanisms of the IFN response driven by lipin‐2 and open new perspectives for the future management of patients with LPIN2 mutations.

show abstract

Section: Discussionmentioning

confidence: 99%

Lipin‐2 regulates the antiviral and anti‐inflammatory responses to interferon

de Pablo,

Meana,

Martínez‐García

et al. 2023

EMBO Reports

View full text Add to dashboard Cite

show abstract

“…Han et al discuss the feasibility of repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents in the context of the virus lifecycle. 13 …”

Section: Repurposing Drugs As Anti-infective Therapiesmentioning

confidence: 99%

Drug repurposing: An effective strategy to accelerate contemporary drug discovery

Zhan

Ouyang

2022

Drug Discovery Today

View full text Add to dashboard Cite

“…Currently, CypD inhibitors have emerged as a potential therapeutic approach for the treatment of AP. [17] Shaanxi Provincial Natural Science Basic Research Program (2022JQ-910).…”

Section: Introductionmentioning

confidence: 99%

Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis

Li,

Liu,

Lai

et al. 2023

Medicine

View full text Add to dashboard Cite

Cyclophilin D (CypD) is a mitochondrial matrix peptidyl prolidase that regulates the mitochondrial permeability transition pore. Inhibition of CypD was suggested as a therapeutic strategy for acute pancreatitis. Peptide inhibitors emerged as novel binding ligand for blocking receptor activity. In this study, we present our computational approach for designing peptide inhibitors of CypD. The 3-D structure of random peptides were built, and docked into the active center of CypD using Rosetta script integrated FlexPepDock module. The peptide displayed the lowest binding energy against CypD was further selected for virtual iterative mutation based on virtual mutagenesis and molecular docking. Finally, the top 5 peptides with the lowest binding energy was selected for validating their affinity against CypD using inhibitory assay. We showed 4 out of the selected 5 peptides were capable for blocking the activity of CypD, while WACLQ display the strongest affinity against CypD, which reached 0.28 mM. The binding mechanism between WACLQ and CypD was characterized using molecular dynamics simulation. Here, we proved our approach can be a robust method for screening peptide inhibitors.

show abstract

Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents

Cited by 16 publications

References 160 publications

Lipin‐2 regulates the antiviral and anti‐inflammatory responses to interferon

Lipin‐2 regulates the antiviral and anti‐inflammatory responses to interferon

Drug repurposing: An effective strategy to accelerate contemporary drug discovery

Rational design peptide inhibitors of Cyclophilin D as a potential treatment for acute pancreatitis

Contact Info

Product

Resources

About