We report a 100‐fold increase in binding affinity of the Tat(48–57) peptide to HIV‐1 transcriptional activator‐responsive element (TAR) RNA by replacing Arg52, an essential and critical residue for Tat's specific binding, with (2S,4S)‐4‐guanidinoproline. The resulting αTat1M peptide is a far superior binder than γTat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)‐4‐amino‐N‐(3‐guanidinopropyl)proline, or even the control Tat peptide (CtrlTat) itself. Our observations are supported by circular dichroism (CD), isothermal titration calorimetry (ITC), gel electrophoresis and UV spectroscopy studies. Molecular dynamics simulations suggest increased interactions between the more compact αTat1M and TAR RNA, relative to CtrlTat. The CD signature of the RNA itself remains largely unchanged upon binding of the peptides. The Tat mimetics further have better cell uptake properties than the control Tat peptide, thus increasing their potential application as specific TAR‐binding molecules.

中文翻译：

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Tat（48–57）肽中具有构象约束的R52精氨酸模拟物的卓越HIV-1 TAR结合剂

我们报告说，通过用（2 S，4 S）‐4‐胍基脯氨酸。所得的αTat1M肽是比γTat1M更好的结合剂，γTat1M包含另一个构象受限的精氨酸模拟物（2 S，4 S）-4-氨基N-（3-胍基丙基）脯氨酸，甚至是对照Tat肽（CtrlTat）本身。圆二色性（CD），等温滴定量热（ITC），凝胶电泳和UV光谱学研究为我们的观察提供了支持。分子动力学模拟表明，相对于CtrlTat，更紧密的αTat1M与TAR RNA之间的相互作用增加。结合肽后，RNA本身的CD标记基本上保持不变。与对照Tat肽相比，Tat模拟物还具有更好的细胞摄取特性，因此增加了其作为特定TAR结合分子的潜在应用。