The antiviral antibiotic feglymycin:: First direct-methods solution of a 1000+equal-atom structure
The antiviral antibiotic feglymycin:: First direct-methods solution of a 1000+equal-atom structure
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DOI：
10.1002/anie.200461933
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Sheldrick, GM
中科院分区：
文献类型：
--
作者：
Bunkóczi, G;Vértesy, L;Sheldrick, GM
尽管近几十年来取得了所有进展，但抗病毒化疗仍然比抗生素治疗细菌感染的效果差得多。人体免疫机能丧失病毒（艾滋病毒）是一个特别成问题的例子，因为它的高度变异性可能会降低疫苗的有效性。虽然现在有许多抗病毒化合物可用于治疗获得性免疫缺陷综合征，但艾滋病毒耐药性的增加需要不断开发新药。发现从链霉菌培养物中分离的13-氨基酸feglymycin（图1）是一种新型肽，其在体外强烈抑制HIV合胞体的形成，并且还报道了对革兰氏阳性菌的弱抗菌活性。[1]基于其独特的氨基酸序列和生物活性，feglymycin代表了一类有前途的新抗生素。Feglymycin含有高百分比的不常见氨基酸，如4-羟基苯甘氨酸和3，5-二羟基苯甘氨酸。还发现含有羟基苯甘氨酸残基的结构相关物抑制HIV复制中的不同步骤。此外，大部分从天然来源分离的抗HIV剂也含有1，3-羟基苯基部分，其是分离的或作为稠环系统的一部分。[2]In本文报道了非格霉素的两种晶型（1和2）的晶体结构。1的晶体衍射到原子分辨率（1.10），相位问题可以通过从头计算直接方法解决，尽管（甚至可能有帮助）完美的半面体孪生。[3]这个结构有大约1033个独特的非氢原子，比以前用直接方法解决的最大的等原子结构（不包含比氧重的原子）大大约50%;等原子结构比包含一些更重原子的结构更难用直接方法解决。衍射至1.40的晶型2的结构可以通过使用非格霉素二聚体（取自1）作为搜索片段的分子置换来解析;它还表现出完美的缺面体孪生。[3]肽的X射线序列证实了从NMR和MS数据推断的，并且所有手性中心的构型都可以被指定;除了两个末端，残基的手性在d和l之间交替。
Despite all the progress in recent decades, antiviral chemotherapy is still much less effective than the treatment of bacterial infections by antibiotics. The human immunodeficiency virus (HIV) represents a particularly problematic case since its high variability is likely to reduce the effectiveness of vaccines. Although many antiviral compounds are now available for the treatment of acquired immunodeficiency syndrome, the increasing resistance of HIV requires the constant development of new drugs. The 13-amino-acid feglymycin (Figure 1), a novel peptide isolated from Streptomyces cultures, was found to strongly inhibit the formation of HIV syncytia in vitro, and a weak antibacterial activity against Gram-positive bacteria has also been reported.[1] Based on its unique amino acid sequence and biological activity, feglymycin represents a promising new class of antibiotics. Feglymycin contains a high percentage of unusual amino acids such as 4-hydroxyphenylglycine and 3, 5-dihydroxyphenylglycine. Structural relatives that contain hydroxyphenylglycine residues have also been found to inhibit diverse steps in the replication of HIV. In addition, a large percentage of anti-HIV agents isolated from natural sources also contains a 1, 3-hydroxyphenyl moiety either detached or as part of a condensed ring system.[2]In this communication we report the crystal structures of two crystal forms (1 and 2) of feglymycin. Crystals of 1 diffracted to atomic resolution (1.10), and the phase problem could be solved by ab initio direct methods despite (or possibly even aided by) perfect merohedral twinning.[3] With about 1033 unique non-hydrogen atoms, this structure is about 50% larger than the largest equal-atom structure (containing no atom heavier than oxygen) previously solved by direct methods; equal-atom structures are much more resistant to solution by direct methods than structures containing a few heavier atoms. The structure of crystal form 2, which diffracted to 1.40, could be solved by molecular replacement using a feglymycin dimer (taken from 1) as search fragment; it also exhibits perfect merohedral twinning.[3] The X-ray sequence of the peptide confirmed that deduced from NMR and MS data, and the configurations of all chiral centers could be assigned; except for the two termini, the chirality of the residues alternates between d and l.