Design and Immunological Evaluation of a Hybrid Peptide as a Potent TLR2 Agonist by Structure-Based Virtual Screening

Abstract

Immunity is a versatile defensive response that is involved in protecting against disease by identifying and destroying self and non-self harmful substances. As a state of temporary or permanent immune dysfunction, immunosuppression can make an organism more susceptible to infection, organ injury, and cancer due to damage to the immune system. It has taken a long time to develop new immunomodulatory agents to prevent and treat immunosuppressive diseases. In recent years, Toll-like receptor 2 (TLR2) agonists have been reported to have profound effects on the immune system, and they are regarded as potent immunomodulatory candidates. TP5 and LL-37, the potent immunomodulatory agents, have been reported to produce a robust innate immune response by binding to TLR2. However, their development has been weakened by several concerns, such as potential cytotoxicity, weak physiological stability and poor immunomodulatory activity. To overcome these challenges, hybridization has been proposed. Therefore, six hybrid peptides (LTPa, LTPb, LTPc, TPLa, TPLb, and TPLc) were designed by combining the full-length TP5 with a characteristic fragment of LL-37 that included LL-37 (13–36), LL-37 (17–29), and LL-37 (13–31). LTPa, the most potent TLR2 agonist, was simply and effectively screened by molecular docking and in vitro experiments. Furthermore, the immunomodulatory effects of LTPa were confirmed by a CTX-immunosuppressed murine model, which demonstrated that LTPa successfully inhibit immunosuppression, increased immune organ indices, enhanced DC maturation, regulated T lymphocyte subsets, and increased cytokine and Ig contents. Our study also revealed that the immunomodulatory effects of LTPa are associated with binding to TLR2, forming TLR2 clusters, and activating the NF-κB signaling pathway.

Dihydroartemisinin regulates immune cell heterogeneity by triggering a cascade reaction of CDK and MAPK phosphorylation

“…10 Several previous studies reported that immunostimulators, such as TLR2 agonists and taurine, can increase spleen weight in CTX-immunosuppressed animals. 22 , 23 Here, we also found that DHA treatment significantly reverted the CTX-induced spleen index reduction, whereas CMC did not show this effect (Fig. 1g, h ).…”

Lipid oxidation in pathophysiology of atherosclerosis: Current understanding and therapeutic strategies

“…LDL/LDL-C (LDL-Cholesterol) mediated initiation of atherosclerosis is the fundamental basis of arterial atheroma development. This is majorly driven by the oxidation of LDL-C – particularly unsaturated fatty acids and their subsequent oxidized/hydroxidized products [ 2 , 4 , 20 , 21 ]. In context to ACVD – the most important LDL undeniably includes arachidonic acid (ArA), a type of ω-6 polyunsaturated fatty acid (PUFA), which is either present as an endogenous phospholipid in biological membranes or through dietary intake of linoleic acid (LnA) or animal proteins [ 14 , 22 ].…”

“…These MDA products are mostly converted from dietary and intrinsic ArA, LnA, and docosahexaenoic acid (DHA) [ 4 , 22 ]. Aldehydes and advanced peroxides promote further oxidative stress and ROS stress, chemotaxis of inflammatory cells, adhesion and migration of cells into blood vessels, cellular proliferation of SMCs and PBMCs, stimulation of IL, IFN, TNF, NF-κB and TGF, and eventual intimal vasoconstriction [ 3 , 4 , 20 , 21 ]. Peroxidation products also inhibit anti-inflammatory prostacyclins (PCs) and nitric oxides (NOs), thereby resulting in the aggravation of platelet activation at the site of inflammation [ 4 ].…”

“…Likewise, lipoxygenase enzymes (15-LOX/5-LOX/12-LOX) oxidize PUFAs to a wide array of unstable hydroperoxides and hydroxy acids including hydroxyeicosatetraenoic acids (HETEs), hydroperoxyeicosatetraenoic acids (HPETEs), hydroxyeicosapentaenoic acids (HEPEs), hydroxyoctadecadienoic acids (HPODEs), 4-hydroxynonenal (4-HNE), LXs, and LTs. These metabolites have been reported to have primary roles in local inflammatory signaling, vascular permeation, epithelial dysfunction, and vasoconstriction [ 14 , 15 , 21 ]. CYP proteins, on the other hand, have a diverse set of roles and produce different lipid epoxides and hydrolysates.…”

“…In contrast to stable PUFAs which generally exist as lipoproteins in conjunction with antioxidants (e.g. : Apolipoprotein a/b), LOO*s are highly unstable and cross biological barriers, which leads to further propagation of oxidant radicals into the cellular domain, and consequently, activation of the stress response and inflammation pathways [ 15 , 20 , 21 ].…”