School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
J Pept Sci. 2010 Aug;16(8):424-9. doi: 10.1002/psc.1258.
The most challenging target in the design of new antimicrobial agents is the development of antibiotic resistance. Antimicrobial peptides are good candidates as lead compounds for the development of novel anti-infective drugs. Here we propose the sequential substitution of each Ala residue present in a lead peptide with known antimicrobial activity by specific amino acids, rationally chosen, that could enhance the activity of the resultant peptide. Taking the fragment 107-115 of the human lysozyme as lead, two-round screening by sequentially replacing both Ala residues (108 and 111) by distinct amino acids resulted in a novel peptide with 4- and 20-fold increased antimicrobial activity against Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213, respectively. These results reinforce the strategy proposed, which, in combination with simple and easy screening tools, will contribute to the rapid development of new therapeutic peptides required by the market.
在新抗菌药物设计中，最具挑战性的目标是开发抗生素耐药性。抗菌肽是开发新型抗感染药物的候选先导化合物。在这里，我们提出通过合理选择的特定氨基酸，依次取代具有已知抗菌活性的先导肽中的每个 Ala 残基，从而增强所得肽的活性。以人溶菌酶的 107-115 片段作为先导肽，通过依次替换两个 Ala 残基（108 和 111）进行两轮筛选，得到一种新型肽，对大肠杆菌 ATCC 25922 和金黄色葡萄球菌 ATCC 29213 的抗菌活性分别提高了 4 倍和 20 倍。这些结果证实了所提出的策略，该策略结合简单易用的筛选工具，将有助于快速开发市场所需的新型治疗性肽。
