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Abstract
The Complement inhibitor K-76 was isolated from the supernatant of the culture broth of the fungus Stachybotrys complementi, nov. sp. K-76. The natural product is a sesquiterpenic dialdehyde which can be partially oxidized to the monocarboxylic acid derivative (K-76 COOH, MX-1), the sodium salt of which is more soluble and less toxic than the natural product. Both, K- 76 and K-76 COOH inhibit Complement activation by the classical and alternative pathways, mainly at the C5 level. Reviewed here are the isolation and total syntheses of the natural product as well as aspects of its Complement inhibitory activity. Approaches to the synthesis of grisan, which bears the BCD skeleton of the natural product, as well as the synthesis of CD-, BCD- and ACD-ring structural analogues of K-76, including the use of natural products as starting materials, and evaluation of their biological activity as Complement inhibitors, are also discussed.
Highlights
The Complement inhibitor K-76 was isolated from the supernatant of the culture broth of the fungus Stachybotrys complementi, nov. sp
The mannose binding lectin (MBL) pathway is triggered by the binding of MBL to repeating carbohydrate residues exposed on target cells
The involvement of the Complement system in the early phases of the inflammatory response and the wide array of pro-inflammatory consequences of Complement activation,23 have made this system an attractive target for therapeutic intervention. This has resulted in the isolation and synthesis of a host of Complement inhibitors,24 as well as the design of new and useful bioactive structures
Summary
Complement activation has several benefits, including provision of resistance towards infectious agents, processing naturally generated immune complexes and developing an optimal humoral immune response. Under certain circumstances and conditions, the Complement system may become activated and, as part of its complex functions, yield undesirable results, including injury, deepening or worsening of a disease. The desirable properties of a broadly applicable anticomplement therapeutic agent, useful in acute and chronic conditions include inexpensiveness, high specificity and very long plasma half-life. It should be active orally and block pathological activation of Complement while causing minimal disruption of the systemic Complement function. There are no currently available low molecular weight oral therapies for temporally targeting undesirable or abnormal Complement system activation without negatively affecting the beneficial functions of Complement or interfering with other complex cascades that Complement is linked to. It is not unlikely to expect that in another two decades or so humankind will have agents that meet most of the desirable properties of an ideal oral Complement inhibitor, enabling effective control of this system in humans
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