Journal
MOLECULES
Volume 22, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/molecules22071054
Keywords
antimicrobial peptides; rational design; molecular dynamics; cyclopeptides; plant pathogens; secondary structure
Funding
- Ministerio de Economia y Competitividad (MINECO) [AGL2009-13255-C02-02/AGR, AGL2012-39880-C02-02, AGL2015-69876-C2-2-R]
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A strategy for the design of antimicrobial cyclic peptides derived from the lead compounds c(KKLKKFKKLQ) (BPC194) and c(KLKKKFKKLQ) (BPC198) is reported. First, the secondary beta-structure of BPC194 and BPC198 was analyzed by carrying out molecular dynamics (MD) simulations. Then, based on the sequence pattern and the beta-structure of BPC194 or BPC198, fifteen analogues were designed and synthesized on solid-phase. The best peptides (BPC490, BPC918, and BPC924) showed minimum inhibitory concentration (MIC) values <6.2 mu M against Pseudomonas syringae pv. syringae and Xanthomonas axonopodis pv. vesicatoria, and an MIC value of 12.5 to 25 mu M against Erwinia amylovora, being as active as BPC194 and BPC198. Interestingly, these three analogues followed the structural pattern defined from the MD simulations of the parent peptides. Thus, BPC490 maintained the parallel alignment of the hydrophilic pairs K-1-K-8, K-2-K-7, and K-4-K-5, whereas BPC918 and BPC924 included the two hydrophilic interactions K-3-Q(10) and K-5-K-8. In short, MD simulations have proved to be very useful for ascertaining the structural features of cyclic peptides that are crucial for their biological activity. Such approaches could be further employed for the development of new antibacterial cyclic peptides.
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