Rational Design of Cyclic Antimicrobial Peptides Based on BPC194 and BPC198

Abstract

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 β-structure of BPC194 and BPC198 was analyzed by carrying out molecular dynamics (MD) simulations. Then, based on the sequence pattern and the β-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 μM against Pseudomonas syringae pv. syringae and Xanthomonas axonopodis pv. vesicatoria, and an MIC value of 12.5 to 25 μM 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 K1–K8, K2–K7, and K4–K5, whereas BPC918 and BPC924 included the two hydrophilic interactions K3–Q10 and K5–K8. 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.

Tryptophan-Rich and Proline-Rich Antimicrobial Peptides

“…Besides, cyclotides are highly stable, retaining their biological activity after boiling and being extremely resistant to enzymatic degradation. BPC194 [c(KKLKKFKKLQ)], is a synthetic cyclic peptide and exhibited biological activity against various plant pathogens such as Erwinia amylovora , Pseudomonas syringae, and Xanthomonas vesicatoria [ 47 ]. Besides, cyclic dipeptides (also known as 2, 5-diketopiperazines) are mainly synthesized by microorganisms and possess diverse biological properties such as antitumor, antifungal, and antibacterial activities.…”

Peptide-Based Drugs and Drug Delivery Systems

“…Cirac et al [ 10 ] were interested in the design of novel AMPs for the treatment of plant diseases in order to substitute the main agents used in crop protection, such as copper derivatives and antibiotics, which are environmental contaminants and may cause development of resistance. The authors employed molecular dynamics (MD) simulations as a tool to recognize the factors that drive formation of stable, partially amphipathic β-structures in cyclic peptides with antimicrobial activity.…”

Engineered Cationic Antimicrobial Peptides (eCAPs) to Combat Multidrug-Resistant Bacteria

“…Another significant concern is the potential for host toxicity. Altogether, we and others have demonstrated that most of these limitations can be significantly overcome by structural design optimization, as shown by engineered peptides [28,38,55,75,104,[118][119][120].…”

“…An important group comprises the primate theta-defensins (e.g., retrocyclins), not found in humans due to a premature stop codon [ 33 , 34 ]. In general, cyclic AMPs are significant for their enhanced stability compared to non-cyclic peptides, which partly explains a considerable interest in their clinical development [ 35 , 36 , 37 , 38 ]. Helical structures can be represented by magainins, cecropins, cathelicidins, and others [ 9 , 10 , 39 , 40 , 41 ].…”