KCF-18
Anti-Inflammatory Peptide
Contents
Sequence:
H-Lys-Cys-Arg-Lys-Glu-Met-Phe-Lys-Gln-Lys-Leu-Pro-Tyr-Val-Tyr-Phe-OH
Molar Weight:
2296.74 g/mol
Molecular Formula:
C107H166N26O26S2
Most Frequent Uses:
- Anti-inflammatory
- Metaflammation support
- Cardiovascular diseases – decreases inflammation in vascular walls
- GUT endotoxin and chronic infections
- Osteoarthritis and conditions involving chronic inflammation
Dosage:
- IV (in 0.9% NS)
- 3 – 0.6 mg/kg (conc. = 1mg/ml)
- Infuse over 30min – 1 hr
Safety and Potential Side Effects/Contraindications:
- KCF-18 peptide administered IV is anecdotally reported safe in recommended dosages.
- As with all injections, redness and pain at the site of injection may be present.
Description
Although therapies have been applied to improve the clinical outcome of patients with severe inflammation through the removal of inflammatory mediators, most approaches have not provided any sustainable benefits for mortality.[i]
KCF-18 inhibits cytokine-induced inflammatory response. It has amphiphilic properties (positively charged and hydrophobic residues) derived from the receptors of proinflammatory cytokines. The lab studies report KCF-18:[ii]
- Binds to cytokines simultaneously, with electrostatic interactions being the dominant mechanism
- Significantly reduces the binding of proinflammatory cytokines (TNF-alpha, IL-6) to their cognate receptors
- Suppresses TNF-α mRNA expression and monocyte binding and transmigration
- Alleviates the infiltration of white blood cells (in a peritonitis mouse model)
Studies support that KCF-18 could remarkably diminish the risk of vascular inflammation by decreasing plasma cytokines release and by directly acting on the vascular endothelium.
[i] Ranieri, VM, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–2064.
[ii] Jiang SJ, et al. A potential peptide derived from cytokine receptors can bind proinflammatory cytokines as a therapeutic strategy for anti-inflammation. Sci Rep. 2019;9(1):2317.
Clinical Research
IPS Level of Evidence
IPS Clinical Pharmacists have developed a method of ranking the studies so that the practitioner can easily discern the level of evidence this study provides to the topic. Levels 1-8 are listed below:
| Level of Evidence | Description | |
| Level 1 | FDA Approved Drug studies | |
| Level 2 | Evidence obtained from systematic review and/or meta-analyses of studies including RCTs and other human studies | |
| Level 3 | Evidence obtained from a RCT | |
| Level 4 | Evidence obtained from a study without randomization | |
| Level 5 | Evidence obtained from case reports | |
| X | Level 6 | Evidence obtained from in vitro human studies |
| X | Level 7 | Evidence obtained from laboratory animal studies |
| Level 8 | Evidence obtained from Opinions or Reviews |
Levels
Level 6
Chang CC, et al. A Multitarget Therapeutic Peptide Derived From Cytokine Receptors Based on in Silico Analysis Alleviates Cytokine-Stimulated Inflammation. Front Pharmacol. 2022;13:853818.
Abstract
Septicemia is a severe inflammatory response caused by the invasion of foreign pathogens. Severe sepsis-induced shock and multiple organ failure are the two main causes of patient death. The overexpression of many proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, is closely related to severe sepsis. Although the treatment of sepsis has been subject to many major breakthroughs of late, the treatment of patients with septic shock is still accompanied by a high mortality rate. In our previous research, we used computer simulations to design the multifunctional peptide KCF18 that can bind to TNF-α, IL-1β, and IL-6 based on the binding regions of receptors and proinflammatory cytokines. In this study, proinflammatory cytokines were used to stimulate human monocytes to trigger an inflammatory response, and the anti-inflammatory ability of the multifunctional KCF18 peptide was further investigated. Cell experiments demonstrated that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors and inhibited the mRNA and protein expressions of TNF-α, IL-1β, and IL-6. It could also reduce the expression of reactive oxygen species induced by cytokines in human monocytes. KCF18 could effectively decrease the p65 nucleus translocation induced by cytokines, and a mice endotoxemia experiment demonstrated that KCF18 could reduce the expression of IL-6 and the increase of white blood cells in the blood stimulated by lipopolysaccharides. According to our study of tissue sections, KCF18 alleviated liver inflammation. By reducing the release of cytokines in plasma and directly affecting vascular cells, KCF18 is believed to significantly reduce the risk of vascular inflammation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8965626/
Jiang SJ, et al. A potential peptide derived from cytokine receptors can bind proinflammatory cytokines as a therapeutic strategy for anti-inflammation. Sci Rep. 2019;9:2317.
Abstract
Chronic inflammation is a pivotal event in the pathogenesis of cardiovascular diseases, including atherosclerosis, restenosis, and coronary artery disease. The efficacy of current treatment or preventive strategies for such inflammation is still inadequate. Thus, new anti-inflammatory strategies are needed. In this study, based on molecular docking and structural analysis, a potential peptide KCF18 with amphiphilic properties (positively charged and hydrophobic residues) derived from the receptors of proinflammatory cytokines was designed to inhibit cytokine-induced inflammatory response. Simulations suggested that KCF18 could bind to cytokines simultaneously, and electrostatic interactions were dominant. Surface plasmon resonance detection showed that KCF18 bound to both tumor necrosis factor-α (TNF-α) and interleukin-6, which is consistent with MM/PBSA binding free energy calculations. The cell experiments showed that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors, suppressed TNF-α mRNA expression and monocyte binding and transmigration, and alleviated the infiltration of white blood cells in a peritonitis mouse model. The designed peptide KCF18 could remarkably diminish the risk of vascular inflammation by decreasing plasma cytokines release and by directly acting on the vascular endothelium. This study demonstrated that a combination of structure-based in silico design calculations, together with experimental measurements can be used to develop potential anti-inflammatory agents.
https://www.nature.com/articles/s41598-018-36492-z
Level 7
Shih HJ, et al. Simultaneous Inhibition of Three Major Cytokines and Its Therapeutic Effects: A Peptide-Based Novel Therapy against Endotoxemia in Mice. J Pers Med. 2021;11(5):436.
Abstract
Three major cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, mediate endotoxemia-induced liver injury. With the similar structures to the binding domains of the three cytokines to their cognate receptors, the novel peptide KCF18 can simultaneously inhibit TNF-α, IL-1β, and IL-6. We elucidated whether KCF18 can alleviate injury of liver in endotoxemic mice. Adult male mice (BALB/cJ) were intraperitoneally (i.p.) administered lipopolysaccharide (LPS, 15 mg/kg; LPS group) or LPS with KCF18 (LKCF group). Mice in the LKCF group received KCF18 (i.p.) at 2 h (0.6 mg/kg), 4 h (0.3 mg/kg), 6 h (0.3 mg/kg), and 8 h (0.3mg/kg) after LPS administration. Mice were sacrificed after receiving LPS for 24 h. Our results indicated that the binding levels of the three cytokines to their cognate receptors in liver tissues in the LKCF group were significantly lower than those in the LPS group (all p < 0.05). The liver injury level, as measured by performing functional and histological analyses and by determining the tissue water content and vascular permeability (all p < 0.05), was significantly lower in the LKCF group than in the LPS group. Similarly, the levels of inflammation (macrophage activation, cytokine upregulation, and leukocyte infiltration), oxidation, necroptosis, pyroptosis, and apoptosis (all p < 0.05) in liver tissues in the LKCF group were significantly lower than those in the LPS group. In conclusion, the KCF18 peptide–based simultaneous inhibition of TNF-α, IL-1β, and IL-6 can alleviate liver injury in mice with endotoxemia.
https://www.mdpi.com/2075-4426/11/5/436
Chen KY, et al. Tumor Necrosis Factor-α Mediates Lung Injury in the Early Phase of Endotoxemia. Pharmaceuticals. 2022;15(3):287.
Abstract
Endotoxemia induces lung injury. We assessed the therapeutic efficacy between triple cytokine (tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], and IL-6) inhibition (mediated by KCF18 peptide) and single cytokine (TNF-α) inhibition (mediated by SEM18 peptide) on alleviating lung injury in the early phase of endotoxemia. Mice receiving endotoxin (Endo group), endotoxin plus KCF18 (EKCF group), or endotoxin plus SEM18 (ESEM) were monitored and euthanized at 24 h after endotoxin. Our data demonstrated altered lung function (decreases in tidal volume, minute ventilation, and dynamic compliance; and by contrast, increases in airway resistance and end expiration work) and histology (increases in injury scores, leukocyte infiltration, vascular permeability, and tissue water content) in the Endo group with significant protection observed in the EKCF and ESEM groups (all p < 0.05). Levels of inflammation (macrophage activation and cytokine upregulations), oxidation (lipid peroxidation), necroptosis, pyroptosis, and apoptosis in EKCF and ESEM groups were comparable and all were significantly lower than in the Endo group (all p < 0.05). These data demonstrate that single cytokine TNF-α inhibition can achieve therapeutic effects similar to triple cytokines TNF-α, IL-1β, and IL-6 inhibition on alleviating endotoxin-induced lung injury, indicating that TNF-α is the major cytokine in mediating lung injury in the early phase of endotoxemia.