TAT-HSA-α-MSH fusion protein with extended half-life inhibits tumor necrosis factor-α in brain inflammation of mice

Abstract

Neuroinflammation constitutes a principal process involved in the progression of various central nervous system (CNS) disorders, including Parkinson's disease, Alzheimer's disease, ischemic stroke, and traumatic brain injury. The safety and efficacy of potential neuroprotective therapeutic agents is controversial and limited. Alpha-melanocyte-stimulating hormone (α-MSH) as a tridecapeptide derived from pro-opiomelanocortin displays potent anti-inflammatory and protective effects with a wide therapeutic window in brain damage. However, it is difficult to deliver effective concentrations of α-MSH into brain tissue via nondirect application. Besides, the half-life of the tridecapeptide is only a few minutes. In the present study, we generated a novel TAT-HSA-α-MSH by genetically fusing α-MSH with N-terminus 11-amino acid protein transduction domain of the human immunodeficiency virus Tat protein (TAT) and human serum albumin (HSA), which showed favorable pharmacokinetic properties and can effectively cross the blood brain barrier (BBB). The findings showed that TAT-HSA-α-MSH significantly inhibits NF-κB activation in human glioma cells A172 and tumor necrosis factor-α (TNF-α) production in experimental brain inflammation. These results indicate that TAT-HSA-α-MSH may be a potential therapeutic agent for treating neuroinflammation which plays a fundamental role in CNS disorders.

Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke

“…The half-life for TAT-conjugated peptides is cargo-dependent and has been found to range from 1 h to as high as 18 h (Krosl et al, 2003;Bach et al, 2012;Wang et al, 2016). Our two-photon data indicated that the FitC-tagged TAT-C1aB remained detectable above baseline in the CNS vasculature for Ն2 h after intraperitoneal injection (Fig.…”

αMSH inhibits adipose inflammation via reducing FoxOs transcription and blocking Akt/JNK pathway in mice

“…αMSH as a tridecapeptide derived from POMC displays potent anti-inflammatory role in many tissues and has protective effects on therapies in brain damage, liver or lung fibrosis, skin inflammation and chronic adipose inflammation. The fusion protein TAT-HSA-α-MSH inhibits NF-κB activation in human and TNFα production in mice to prevent brain inflammation in central nervous system (CNS) disorders [ 34 , 35 ]. αMSH has also been confirmed to inhibit antigen-induced allergic skin inflammation, abolish monocytes adhesion to vascular endothelium, attenuate bleomycin-induced pulmonary inflammation, blunt adipose oxidative stress and inflammation, and protect from adipose tissue apoptosis and fat deposition [ 24 , 36 – 40 ].…”

Peptide regulation of cofilin activity in the CNS: A novel therapeutic approach for treatment of multiple neurological disorders

“…Overexpression of a DS cell adhesion molecule has important consequences in neuronal proliferation, maturation, and synaptogenesis that appear to be mediated via a Pak-dependent pathway activating LIMK and inactivating cofilin (Perez-Nunez et al, 2016). Another chromosome 21 overexpressed protein, DS critical region 1 protein, a regulator of calcineurin, modulates axonal outgrowth and brain derived neurotrophic factor-induced growth cone guidance via local protein synthesis and cofilin phosphoregulation (Gehler et al, 2004; Wang W. et al, 2016). Furthermore, DS critical region 1 protein also interacts with Fragile X mental retardation protein, with which it may share a common pathway leading to intellectual disability (Wang et al, 2012).…”

“…Modification of peptide drugs to overcome this is part of the drug design process. Possible modifications include incorporation of D-stereoisomer amino acids (such as in the peptide DAPTA), N-terminal acetylation, C-terminal amidylation, or fusion to a very stable protein such as human serum albumin (Weinstock et al, 2012; Wang et al, 2016). The peptides used in the above studies were i.v.…”