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LT8317 is a lipidated analog of the anti-fibrotic peptide M10, containing the bioactive sequence TRPASFWETS fused to an N-terminal Palmitoyl-spacer moiety. The parent M10 peptide is derived from the intracellular cytoplasmic domain of the hepatocyte growth factor receptor (c-MET) and was identified as a naturally occurring caspase-3 cleavage product with potent anti-fibrotic activity.
Fibrosis is a common pathological process underlying numerous chronic diseases, including pulmonary fibrosis, systemic sclerosis, liver fibrosis, kidney fibrosis, and cardiac remodeling. Excessive activation of the transforming growth factor-beta (TGF-β) pathway leads to persistent fibroblast activation and abnormal extracellular matrix deposition. The M10 peptide was discovered as an endogenous inhibitor of this fibrotic process and has attracted significant interest as a potential anti-fibrotic therapeutic lead.
Published studies have demonstrated that M10 suppresses collagen production in activated fibroblasts and attenuates fibrotic responses in experimental models. Mechanistically, M10 binds directly to the MH2 domain of Smad2, thereby inhibiting TGF-β-induced Smad2 phosphorylation and reducing downstream expression of pro-fibrotic genes, including type I collagen and connective tissue growth factor (CTGF).
The anti-fibrotic activity of M10 appears to function downstream of c-MET signaling. In patients carrying the D1398G variant of c-MET, impaired generation of endogenous M10 has been associated with increased susceptibility to fibrotic disease progression. Administration of synthetic M10 has been shown to restore anti-fibrotic signaling in cellular and animal models, highlighting the importance of this pathway in tissue remodeling and fibrosis control.
Why Palmitoylate M10?
Although the parent M10 peptide exhibits promising biological activity, short peptides often suffer from rapid clearance and limited stability in biological systems. To address these challenges, LT8317 incorporates an N-terminal palmitic acid modification linked through a spacer.
Palmitoylation is a widely used strategy in peptide drug discovery and development. Attachment of a long-chain fatty acid can:
- Increase plasma protein (albumin) binding
- Improve peptide stability against enzymatic degradation
- Enhance membrane interaction and cellular uptake
- Extend circulation half-life in vivo
- Improve tissue exposure and biodistribution
- Facilitate evaluation of therapeutic potential in animal studies
The incorporated linker serves as a hydrophilic spacer, separating the lipid moiety from the bioactive M10 sequence and reducing steric interference while maintaining favorable physicochemical properties.
Structural Design of LT8317
Palmitoyl ── Spacer ── TRPASFWETS (M10)
Lipid Anchor → Improved Stability & Exposure → Anti-Fibrotic Peptide Domain
Research Applications
LT8317 may be useful for investigators studying:
- TGF-β/Smad signaling pathways
- Fibroblast activation and extracellular matrix regulation
- Systemic sclerosis-associated interstitial lung disease (SSc-ILD)
- Idiopathic pulmonary fibrosis (IPF)
- Fibrotic remodeling in liver, kidney, skin, and cardiac tissues
- Peptide lipidation and delivery optimization
- Pharmacokinetic and biodistribution studies
- Novel anti-fibrotic therapeutic development
Scientific Background
The hepatocyte growth factor (HGF)/c-MET signaling axis is widely recognized as a natural anti-fibrotic pathway. Loss of c-MET activity promotes fibroblast activation and extracellular matrix accumulation. The M10 peptide represents a key downstream mediator of c-MET's protective effects and has been shown to significantly reduce collagen synthesis and fibrosis progression in preclinical studies.
In bleomycin-induced pulmonary fibrosis models, treatment with M10 resulted in significant reductions in lung collagen deposition and histological fibrosis scores. These findings support the continued investigation of M10-derived analogs as research tools and potential therapeutic leads for chronic fibrotic diseases.
References
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Atanelishvili I, Akter T, Kaplun L, et al.
M10, a hepatocyte growth factor receptor MET-derived peptide, interacts with Smad2 and exerts anti-fibrotic activity in vitro and in vivo.
Translational Research. 2015.
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Akter T.
Potential Therapeutic Effects of a 10 Amino Acid Peptide, M10, in Scleroderma Associated Interstitial Lung Disease.
Medical University of South Carolina Dissertation. 2018.
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Müller C, et al.
Fatty acid modification of peptides and proteins for therapeutic applications.
Pharmaceutics. 2022.
FOR RESEARCH USE ONLY. NOT FOR HUMAN OR VETERINARY USE. NOT FOR USE IN DIAGNOSTIC OR CLINICAL PROCEDURES.
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