Roles of inter- and intramolecular tryptophan interactions in membrane-active proteins revealed by racemic protein crystallography

Lander, Alexander J.; Mercado, Laura Domínguez; Li, Xuefei; Taily, Irshad Maajid; Findlay, Brandon; Jin, Yi; Luk, Louis Y. P.

doi:10.1038/s42004-023-00953-y

Cited by 7 publications

(6 citation statements)

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“…The suggested alteration for this peptide was based on the relationship between tryptophan and antimicrobial activity. This amino acid plays a crucial role in proteins and peptides interacting with membranes. , In addition, several studies show a relationship between this amino acid and increased antimicrobial activity without increasing hemolytic activity. − …”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…This amino acid is crucial for proteins and peptides to interact with membranes. 13,14 This simple exchange vastly increased the activity against Gram-negative bacteria, highlighting the importance of the structure−activity relationship.…”

Section: ■ Introductionmentioning

confidence: 99%

“…An image providing the location of p-BthTX-I in the protein Bothropstoxin-I is provided in Figure , as well as the alignment between the previously studied peptide and the new analogue p-BthW. This amino acid is crucial for proteins and peptides to interact with membranes. , This simple exchange vastly increased the activity against Gram-negative bacteria, highlighting the importance of the structure–activity relationship.…”

Section: Introductionmentioning

confidence: 99%

“…This amino acid plays a crucial role in proteins and peptides interacting with membranes. 13,14 In addition, several studies show a relationship between this amino acid and increased antimicrobial activity without increasing hemolytic activity. 14−17 The initial assessment of the newly synthesized peptide was its comparison with its previously evaluated analogue for antibacterial activity and cytotoxicity.…”

Section: ■ Introductionmentioning

confidence: 99%

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Optimizing Bothropstoxin-I-Derived Peptides: Exploring the Antibacterial Potential of p-BthW

Marinho Righetto,

Alves Santos-Filho,

Oliveira Catarin Nunes

et al. 2024

ACS Omega

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Antimicrobial peptides are an emerging class of antibiotics that present a series of advantageous characteristics such as wide structural variety, broad spectrum of activity, and low propensity to select for resistance. They are found in all classes of life as defense molecules. A group of peptides derived from the protein Bothropstoxin-I has been previously studied as an alternative treatment against multi-drug-resistant bacteria. The peptide p-BthTX-I (sequence: KKYRYHLKPFCKK) and its homodimer, linked by disulfide oxidation through the residues of Cys11 and the serum degradation product [sequence: (KKYRYHLKPFC)2], were evaluated and showed similar antimicrobial activity. In this study, we synthesized an analogue of p-BthTX-I that uses the strategy of Fmoc-Lys(Fmoc)-OH in the C-terminal region for dimerization and tryptophan for all aromatic amino acids to provide better membrane interactions. This analogue, named p-BthW, displayed potent antibacterial activity at lower concentrations and maintained the same hemolytic levels as the original molecule. Our assessment revealed that p-BthW has a quick in vitro bactericidal action and prolonged post-antibiotic effect, comparable to the action of polymyxin B. The mode of action of p-BthW seems to rely not only on membrane depolarization but also on necrosis-like effects, especially in Gram-negative bacteria. Overall, the remarkable results regarding the propensity to develop resistance reaffirmed the great potential of the developed molecule.

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