Lam K S, Salmon S E, Hersh E M, Hruby V J, Kazmierski W M, Knapp R J
Arizona Cancer Center, Tucson.
Nature. 1991 Nov 7;354(6348):82-4. doi: 10.1038/354082a0.
Our aim was to improve techniques for drug development by facilitating the identification of small molecules that bind with high affinity to acceptor molecules (for example, cell-surface receptors, enzymes, antibodies) and so to mimic or block their interaction with the natural ligand. Previously such small molecules have been characterized individually on a serial basis. The systematic synthesis and screening of peptide libraries of defined structure represents a new approach. For relatively small libraries, predetermined sequence variations on solid-phase supports have been used, and large libraries have been produced using a bacteriophage vector into which random oligodeoxynucleotide sequences have been introduced, but these techniques have severe limitations. Here we investigate an alternative approach to synthesis and screening of peptide libraries. Our simple methodology greatly enhances the production and rapid evaluation of random libraries of millions of peptides so that acceptor-binding ligands of high affinity can be rapidly identified and sequenced, on the basis of a 'one-bead, one-peptide' approach.
我们的目标是通过促进对与受体分子（如细胞表面受体、酶、抗体）具有高亲和力结合的小分子的鉴定，从而改进药物开发技术，进而模拟或阻断它们与天然配体的相互作用。以前，此类小分子是逐个进行表征的。对确定结构的肽库进行系统合成和筛选代表了一种新方法。对于相对较小的文库，已使用固相支持物上的预定序列变异，而大型文库则是利用已引入随机寡脱氧核苷酸序列的噬菌体载体构建的，但这些技术存在严重局限性。在此，我们研究了一种用于肽库合成和筛选的替代方法。我们简单的方法极大地提高了数百万肽的随机文库的产量和快速评估能力，从而能够基于“一个珠子，一个肽”的方法快速鉴定和测序高亲和力的受体结合配体。
