Bell A, McSteen P M, Cebrat M, Picur B, Siemion I Z
Department of Microbiology, Moyne Institute, Trinity College, Dublin 2, Ireland.
Acta Pol Pharm. 2000 Nov;57 Suppl:134-6.
Cyclolinopeptide A (CLA) is an immunosuppressive peptide of the sequence c-(-Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), isolated from linseed. Since another cyclic, hydrophobic, immunosuppressive peptide, cyclosporin A, has potent antimalarial activity, CLA and a series of its analogues were synthesized on solid phase and tested for inhibition of the human malarial parasite Plasmodium falciparum in culture. The results were compared with the influence of these agents on humoral and cellular immune responses. There was no clear correlation between the structure of the peptides, their immunosuppressive activity, and their antimalarial activity. However, the antimalarial activity of the peptides was apparently connected with the strong hydrophobic nature of CLA. Substitution of a less hydrophobic residue into the peptide chain led to a decrease in or even loss of detectable activity, although such peptides retained the immunosuppressive properties. A possible explanation is that the antimalarial effect of CLA and analogues may result from their influence on cell membranes rather than on some specific receptor such as cyclophilin. In agreement with this idea, binding of CLA to purified P. falciparum cyclophilin was not detected except at very high concentrations. Substitution of D-aromatic residues into the CLA molecule led to a decrease in immunosuppressive activity but had little effect on antimalarial activity, which for these peptides was of the same order as for CLA. We have therefore demonstrated that the cyclolinopeptides are a class of compound not previously shown to have antimalarial activity, and that in a series of analogues there was no correlation between antimalarial and immunosuppressive effects.
环亚麻肽A（CLA）是一种免疫抑制肽，其序列为c-(-Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-)，从亚麻籽中分离得到。由于另一种环状、疏水的免疫抑制肽环孢菌素A具有强大的抗疟活性，因此在固相上合成了CLA及其一系列类似物，并测试了它们对培养的人类疟原虫恶性疟原虫的抑制作用。将结果与这些药物对体液和细胞免疫反应的影响进行了比较。肽的结构、免疫抑制活性和抗疟活性之间没有明显的相关性。然而，这些肽的抗疟活性显然与CLA的强疏水性有关。将疏水性较低的残基取代到肽链中会导致可检测活性降低甚至丧失，尽管这些肽保留了免疫抑制特性。一种可能的解释是，CLA及其类似物的抗疟作用可能是由于它们对细胞膜的影响，而不是对某些特定受体如亲环蛋白的影响。与此观点一致，除了在非常高的浓度下，未检测到CLA与纯化的恶性疟原虫亲环蛋白的结合。将D-芳香族残基取代到CLA分子中会导致免疫抑制活性降低，但对抗疟活性影响不大，这些肽的抗疟活性与CLA相当。因此，我们证明了环亚麻肽是一类以前未显示具有抗疟活性的化合物，并且在一系列类似物中，抗疟作用和免疫抑制作用之间没有相关性。
