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首页> 外文期刊>Journal of Medicinal Chemistry >Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: Insight into the binding mode of the enzyme
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Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: Insight into the binding mode of the enzyme

机译：HIV-1整合酶肽抑制剂的基于序列的设计和发现：洞悉酶的结合模式

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摘要

Integration of viral DNA into the host chromosome is an essential step in the HIV life cycle. This process is mediated by integrase (IN), a 32 kDa viral enzyme that has no mammalian counterpart, rendering it an attractive target for antiviral drug design. Herein, we present a novel approach toward elucidating "hot spots" of protein-protein or protein-nucleic acid interactions of IN through the design of peptides that encompass conserved amino acids and residues known to be important for enzymatic activity. We designed small peptides (7 - 17 residues) containing at least one amino acid residue that is important for IN catalytic activities (3'-processing and strand transfer) or viral replication. All these peptides were synthesized on solid phase by fluorenylmethoxycarbonyl (Fmoc) chemistry and evaluated for their inhibition of IN catalytic activities. Such specific sites of interest (i.e., protein-DNA or protein-drug interactions) could potentially be used as drug targets. This novel "sequence walk" strategy across the entire 288 residues of IN has allowed the identification of two peptides NL-6 and NL-9 with 50% inhibitory concentration (IC50) values of 2.7 and 56 AM for strand transfer activity, respectively. Amino acid substitution analysis on these peptides revealed essential residues for activity, and the rational truncation of NL-6 produced a novel hexapeptide (peptide NL6-5) with inhibitory potency equal to that of the parent dodecapeptide (peptide NL-6). More significantly, the retroinverso analogue of NL-6 (peptide RDNL-6) in which the direction of the sequence is reversed and the chirality of each amino acid residue is inverted displayed improved inhibitory potency against 3'-processing of HIV-1 IN by 6-fold relative to the parent NL-6, serving as a metabolically stable derivative for further in vitro and in vivo analyses.
机译：病毒DNA整合入宿主染色体是HIV生命周期中必不可少的一步。这个过程是由整合酶（IN）介导的，整合酶是一种32 kDa的病毒酶，没有哺乳动物的对应物，使其成为抗病毒药物设计的有吸引力的靶标。本文中，我们提出了一种新颖的方法，旨在通过设计包含保守氨基酸和已知对酶活性重要的残基的肽来阐明IN的蛋白质-蛋白质或蛋白质-核酸相互作用的“热点”。我们设计了含有至少一个氨基酸残基的小肽段（7-17个残基），这些残基对IN催化活性（3'-加工和链转移）或病毒复制很重要。所有这些肽都是通过芴基甲氧基羰基（Fmoc）化学方法在固相上合成的，并评估了它们对IN催化活性的抑制作用。这样的特定目的位点（即蛋白质-DNA或蛋白质-药物相互作用）可以潜在地用作药物靶标。跨IN的整个288个残基的这种新颖的“序列步移”策略已允许鉴定两种肽NL-6和NL-9，分别具有2.7和56 AM的50％抑制浓度（IC50）值以用于链转移活性。这些肽段的氨基酸取代分析显示了活性的必要残基，NL-6的合理截断产生了一种新的六肽（肽NL6-5），其抑制能力与亲本十二肽（肽NL-6）相等。更重要的是，NL-6的逆转类似物（肽RDNL-6）的序列方向相反，每个氨基酸残基的手性相反，其逆转类似物显示出对HIV-1 IN的3'加工的抑制力提高。相对于母体NL-6是6倍，是代谢稳定的衍生物，可用于进一步的体外和体内分析。

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