Marasco Daniela, Perretta Giuseppe, Sabatella Marco, Ruvo Menotti
Istituto di Biostrutture e Bioimmagini del CNR, via Mezzocannone 16, Naples, Italy.
Curr Protein Pept Sci. 2008 Oct;9(5):447-67. doi: 10.2174/138920308785915209.
Combinatorial preparation and HTS of arrays of compounds have increased the speed of drug discovery. A strong impulse in this field has come by the introduction of the solid phase synthesis method that, through automation and miniaturization, has paved the way to the preparation of large collections of compounds in compact and trackable formats. Due to the well established synthetic procedures, peptides have been largely used to develop the basic concepts of combinatorial chemistry and peptide libraries are still successfully employed in screening programs. However, peptides generally do not fulfil the requirements of low conformational flexibility, stability and bioavailability needed for good drug candidates and peptide leads with high potency and selectivity are often made "druggable" by conversion to more stable structures with improved pharmacological profiles. Such an approach makes the screening of peptide libraries still a valuable tool for drug discovery. We propose here a panoramic review of the most common methods for the preparation and screening of peptide libraries and the most interesting findings of the last decade. We also report on a new approach we follow in our laboratory that is based on the use of "simplified" libraries composed by a minimum number of non-redundant amino acids for the assembly of short peptides. The choice of amino acids is dictated by diversity in lipophilicity, MW, charge and polarity. Newly identified active sequences are then modified by preparing new variants containing analogous amino acids, so that the chemical space occupied by the excluded residues can be explored. This approach offers the advantage of simplifying the synthesis and deconvolution of libraries and provides new active compounds with a molecular size similar to that of small molecules, to which they can be easily converted.
化合物阵列的组合制备和高通量筛选提高了药物发现的速度。该领域的一个强大推动力来自固相合成方法的引入，该方法通过自动化和小型化，为以紧凑且可追踪的形式制备大量化合物库铺平了道路。由于合成程序成熟，肽已被广泛用于发展组合化学的基本概念，肽库仍成功应用于筛选项目。然而，肽通常不能满足优秀药物候选物所需的低构象灵活性、稳定性和生物利用度的要求，具有高效力和选择性的肽先导物通常通过转化为具有改善药理学特性的更稳定结构而变得“可成药”。这种方法使得肽库筛选仍然是药物发现的一个有价值的工具。我们在此对肽库制备和筛选的最常见方法以及过去十年中最有趣的发现进行全景式综述。我们还报告了我们实验室采用的一种新方法，该方法基于使用由最少数量的非冗余氨基酸组成的“简化”库来组装短肽。氨基酸的选择取决于亲脂性、分子量、电荷和极性的多样性。然后通过制备含有类似氨基酸的新变体来修饰新鉴定的活性序列，从而探索被排除残基占据的化学空间。这种方法具有简化库的合成和解卷积的优点，并提供分子大小与小分子相似的新活性化合物，它们可以很容易地转化为小分子。
