Araña Manuel de J, Vallespi Maribel G, Chinea Glay, Vallespi Guillermo V, Rodriguez-Alonso Ingrid, Garay Hilda E, Buurman Wim A, Reyes Osvaldo
Division of Chemistry & Physics, Center for Genetic Engineering and Biotechnology, La Habana, Cuba.
J Endotoxin Res. 2003;9(5):281-91. doi: 10.1179/096805103225002520.
The ability of LPS-binding protein (LBP) to greatly potentiate cell responses to lipopolysaccharide (LPS) may largely contribute to LPS toxicity in sepsis. The study of agents with the capacity to block the interaction between LBP and LPS might improve the understanding of the role of LBP in Gram-negative infections as well as offering new therapeutic tools for septic disorders. Here we confirm the ability of synthetic peptides comprising the human LBP amino acid region 86-108 to interfere with the LBP-LPS interaction. The analysis of selected alanine mutants of a blocking peptide corresponding to the LBP region 86-99 suggests the importance of peptide amphipathicity for the inhibitory activity. The potency of the native peptide and a selected analogue at inhibiting in vitro and in vivo LPS-induced responses was associated with their relative activity in blocking LBP-LPS interaction. It was remarkable that these peptides were at least 500-fold more active in vivo than in vitro. Also, the inhibitory activity of peptides LBP86-99 and LBPK95A seems to be independent of LBP concentrations, a behavior that may be relevant for the potential use of these peptides in septic disorders where LBP serum concentrations are considerably elevated.
脂多糖结合蛋白（LBP）极大地增强细胞对脂多糖（LPS）反应的能力可能在很大程度上导致了脓毒症中LPS的毒性。对具有阻断LBP与LPS相互作用能力的药物进行研究，可能有助于加深对LBP在革兰氏阴性菌感染中作用的理解，并为脓毒症疾病提供新的治疗手段。在此，我们证实了包含人LBP氨基酸区域86 - 108的合成肽干扰LBP - LPS相互作用的能力。对与LBP区域86 - 99对应的一种阻断肽的选定丙氨酸突变体的分析表明，肽的两亲性对抑制活性很重要。天然肽和一种选定类似物在体外和体内抑制LPS诱导反应的效力与它们在阻断LBP - LPS相互作用中的相对活性相关。值得注意的是，这些肽在体内的活性比在体外至少高500倍。此外，肽LBP86 - 99和LBPK95A的抑制活性似乎与LBP浓度无关，这种特性可能与这些肽在LBP血清浓度显著升高的脓毒症疾病中的潜在应用有关。
