Marastoni M, Salvadori S, Balboni G, Spisani S, Gavioli R, Traniello S, Tomatis R
Department of Pharmaceutical Sciences, University of Ferrara, Italy.
Int J Pept Protein Res. 1990 Feb;35(2):81-8. doi: 10.1111/j.1399-3011.1990.tb00239.x.
Acquired immunodeficiency syndrome (AIDS) is initiated by the attachment of the human immunodeficiency virus (HIV) to a surface glycoprotein CD4 present on T4 helper/inducer lymphocytes, monocytes/macrophages and other cells. A simple octapeptide (H-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-OH, peptide T) seems to inhibit HIV infectivity and to activate human monocyte chemotaxis. In order to study in vitro metabolic stability and structure-activity relationships, peptide T and a number of analogues were prepared and tested on human monocytes by chemotactic assay. Peptide T and the shorter fragments T(3-8)-OH and T(4-8)-OH displayed potent bioactivity (maximal chemotactic activity in the range 10(-11)-10(-10) M). The C-terminal heptapeptide showed a reduction of potency, while further truncations at N-terminus of T(4-8)-OH abolished the biological action. In the octapeptide series, whereas the alpha-amino butyric acid (Abu) substitution for Thr4 was well tolerated, the same "slight" structural change at Thr5 or Thr8 was very detrimental. Finally, [D-Asn6]T(1-8)-OH analogue has low chemotactic activity. All these results indicate that i) the C-terminal pentapeptide is the minimum sequence required for bioactivity, ii) residues 5 to 8 appear to play a crucial biological role, iii) peptide T chemotaxis is mediated, at least in part, through the polar properties of Thr side chains at the critical positions 5 and 8, while the Thr4 does not interfere with biological characteristics of peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
获得性免疫缺陷综合征（艾滋病）是由人类免疫缺陷病毒（HIV）附着于T4辅助/诱导淋巴细胞、单核细胞/巨噬细胞及其他细胞表面存在的糖蛋白CD4而引发的。一种简单的八肽（H-丙氨酸-丝氨酸-苏氨酸-苏氨酸-苏氨酸-天冬酰胺-酪氨酸-苏氨酸-OH，肽T）似乎能抑制HIV感染性并激活人类单核细胞趋化性。为了研究体外代谢稳定性和构效关系，制备了肽T及一些类似物，并通过趋化性测定在人类单核细胞上进行测试。肽T以及较短的片段T(3 - 8)-OH和T(4 - 8)-OH表现出强大的生物活性（最大趋化活性在10(-11)-10(-10) M范围内）。C末端七肽的活性有所降低，而T(4 - 8)-OH在N末端进一步截短则消除了生物活性。在八肽系列中，用α-氨基丁酸（Abu）取代苏氨酸4耐受性良好，而在苏氨酸5或苏氨酸8处相同的“轻微”结构变化则非常有害。最后，[D-天冬酰胺6]T(1 - 8)-OH类似物具有较低的趋化活性。所有这些结果表明：i）C末端五肽是生物活性所需的最小序列；ii）第５至８位残基似乎起着关键的生物学作用；iii）肽T的趋化性至少部分是通过关键位置5和8处苏氨酸侧链的极性特性介导的，而苏氨酸4不影响肽的生物学特性。（摘要截短于250字）
