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Targeting MyD88: Therapeutic mechanisms and potential applications of the specific inhibitor ST2825

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Abstract

Background

Myeloid differentiation factor-88 (MyD88) is a crucial adapter protein that coordinates the innate immune response and establishes an adaptive immune response. The interaction of the Toll/Interleukin-1 receptor (IL-1R) superfamily with MyD88 triggers the activation of various signalling pathways such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), promoting the production of a variety of immune and inflammatory mediators and potentially driving the development of a variety of diseases.

Objective

This article will explore the therapeutic potential and mechanism of the MyD88-specific inhibitor ST2825 and describe its use in the treatment of several diseases. We envision future research and clinical applications of ST2825 to provide new ideas for the development of anti-inflammatory drugs and disease-specific drugs to open new horizons for the prevention and treatment of related inflammatory diseases.

Materials and methods

This review analysed relevant literature in PubMed and other databases. All relevant studies on MyD88 inhibitors and ST2825 that were published in the last 20 years were used as screening criteria. These studies looked at the development and improvement of MyD88 inhibitors and ST2825.

Results

Recent evidence using the small-molecule inhibitor of ST2825 has suggested that blocking MyD88 activity can be used to treat diseases such as neuroinflammation, inflammatory diseases such as acute liver/kidney injury, or autoimmune diseases such as systemic lupus erythematosus and can affect transplantation immunity. In addition, ST2825 has potential therapeutic value in B-cell lymphoma with the MyD88 L265P mutation.

Conclusion

Targeting MyD88 is a novel therapeutic strategy, and scientific research is presently focused on the development of MyD88 inhibitors. The peptidomimetic compound ST2825 is a widely studied small-molecule inhibitor of MyD88. Thus, ST2825 may be a potential therapeutic small-molecule agent for modulating host immune regulation in inflammatory diseases and inflammatory therapy.

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Abbreviations

AMI:

Acute myocardial infarction

AP-1:

Activator protein-1

Arg:

Arginine

Asp:

Aspartic acid

BMDCs:

Bone marrow-derived dendritic cells

BTK:

Bruton’s tyrosine kinase

BUN:

Blood urea nitrogen

CpG:

Hypermethylated DNA

CLP:

Caecal ligation puncture

COX:

Cyclooxygenase

DAMPs:

Damage-associated molecular patterns

DD:

Death domain

DLBCL:

Diffuse large B-cell lymphoma

DMARDs:

Anti-rheumatic drugs

Fe2O3 NPs:

Iron oxide nanoparticles

Gly:

Glycine

HMGB1:

High mobility histone 1

HSC:

Hepatic stellate cells

ICAM-1:

Intercellular adhesion factor-1

ID:

Intermediate domain

IEC:

Intestinal epithelial cell

IFN:

Interferon

IL:

Interleukin

IL-1R:

Interleukin-1 receptor

IRAK:

Interleukin-1 receptor-associated kinase

IκB:

κB inhibitor protein

Leu:

Leucine

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemotactic protein-1

MMP:

Matrix metalloproteinase

MyD88:

Myeloid differentiation factor-88

NAD(P)H:

Nicotinamide adenine dinucleotide

NF-κB:

Nuclear factor-κB

NLRP:

Nod-like receptor protein

NO:

Nitric oxide

PAMP:

Pathogen-associated molecular pattern

PBMC:

Peripheral blood mononuclear cell

PC:

Plasma cell

PM:

Particulate matter

PMA:

Phorbol 12-myristate 13-acetate

PQ:

Paraquat

Pro:

Proline

PRR:

Pattern-recognition receptor

Prx2:

Peroxiredoxin 2

RA:

Rheumatoid arthritis

rhIL:

Recombinant human interleukin

SAH:

Subarachnoid hemorrhage

Scr:

Serum creatinine

SLE:

Systemic lupus erythematosus

SREBP-2:

Sterol regulatory element-binding protein-2

TBI:

Traumatic brain injury

Thr:

Threonine

TIR:

Translation initiation region

TLR:

Toll-like receptor

TNF:

Tumour necrosis factor

Val:

Valine

VEGF:

Vascular endothelial growth factor

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Acknowledgements

This work was supported by the Youth Program of National Natural Science Foundation of China (No. 81500169), the Hunan Province Key Laboratory of Tumour Cellular & Molecular Pathology (2016TP1015), and the Key Project of Hunan Provincial Health Commission (20201921).

Funding

This work was supported by the Youth Program of National Natural Science Foundation of China (Grant No. 81500169), the Hunan Provincial Groundbreaking Platform Open Fund of University of South China (Grant No. 19K080), and the Student Research Learning and Innovative Experimental Project of the University of South China (Grant Nos. 20155760439 and X2019141).

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  1. Hengyang Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, People’s Republic of China

    Meiqi Liu, Wenyan Kang, Zhizhong Hu, Chengkun Wang & Yang Zhang

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ML is responsible for writing the article. WK and ZH are responsible for picture modification and article format adjustment. YZ and CW are responsible for the direction and core of the article.

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Liu, M., Kang, W., Hu, Z. et al. Targeting MyD88: Therapeutic mechanisms and potential applications of the specific inhibitor ST2825. Inflamm. Res. 72, 2023–2036 (2023). https://doi.org/10.1007/s00011-023-01801-4

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