Endotoxin-binding peptides

In the present manuscript, we will discuss the mechanism by which endotoxin initiates the sepsis cascade, the rationale for targeting LPS, and the most significant treatments that have been studied antibodies, vaccines, binding peptides, lipid A analog, phospholipids, and polymyixin B hemoperfusion. 

Adsorption (membrane binding) is one mechanism by which hydrophobic compounds such as endotoxins, cytokines, peptides, growth factors, and proteins may be removed... 

The polymyxins are a group of basic peptides active against gram-negative bacteria and include polymyxin and polymyxin E (colistin). Polymyxins act like cationic detergents. They attach to and disrupt bacterial cell membranes. They also bind and inactivate endotoxin. Gram-positive organisms, proteus, and neisseria are resistant. 

Non-vaccine generated anti-endotoxin reagents that bind and/or neutralize LPS, such as bactericidal permeability increasing protein (BPI), endotoxin neutralizing protein (ENP), and cationic peptide 18 conjugated to immunoglobulin G (CAP 18-IgG) have been developed for the adjunctive therapy of sepsis, but only BPI has progressed to clinical trials (Levin et al., 2000). 

The gold standard for anti-endotoxin peptides is Polymyxin B (PMB), a small cyclic lipopep-tide (O Fig. 17). It neutralizes LPS very efficiently, and has been shown to employ a two-step binding process where it first attaches to the LPS by electrostatic interactions and then inserts its acyl chain into the lipid layer. PMB is used only topically because it is neurotoxic. However, there have been many attempts to design analogs with lower toxicity [245,246,247]. Synthetic anti-endotoxin peptides (SAEP) based on Polymyxin B have been engineered to have low toxicity while retaining the in vitro and in vivo detoxification ability of PMB. Furthermore,... 

A-B Toxins are bacterial toxins composed of two peptide chains one (B) that binds to the invaded cell surface, and the other (A) containing the toxin which is then taken-up into the cell. Some examples of exotoxins secreted by the bacteria into the surrounding medium and highly toxic to certain tissues are pathogens causing botuiism (Clostridium botulinum), tetanus (Clostridium tetani) and diptheria (Corynebacterium diphtheria. An example of an A-B endotoxin is Vibrio cholerae. Botulinum toxin and tetanus toxin have their main toxic actions on neuronal tissues, so are described at NEUROTOXINS. 

The antiendotoxin activity of cationic peptides is also related to the above uptake mechanism. Endotoxin is in fact LPS, or more precisely the lipid A portion of LPS. As mentioned above, cationic peptides bind to polyanionic LPS (70.128,129). The binding is of high affinity and cooperative (70). This binding can neutralize the ability of LPS to induce TNF in macrophage cell lines or in a murine model, and it reduces endotoxin mortality in galactosamine-sei isitized mice (130,131). 

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