The prompt appearance of multiantibiotic-resistant bacteria necessitates finding alternative treatments that can attenuate bacterial infections while minimizing the rate of antibiotic resistance development. Streptococcus pneumoniae , a notorious human pathogen, is responsible for severe antibiotic-resistant infections. Its pathogenicity is influenced by a cell-density communication system, termed quorum sensing (QS). As a result, controlling QS through the development of peptide-based QS modulators may serve to attenuate pneumococcal infections. Herein, we set out to evaluate the impact of the introduction of bulkier, nonproteogenic side-chain residues on the hydrophobic binding face of CSP1 to optimize receptor-binding interactions in both of the S. pneumoniae specificity groups. Our results indicate that these substitutions optimize the peptide–protein binding interactions, yielding several pneumococcal QS modulators with high potency. Moreover, pharmacological evaluation of lead analogs revealed that the incorporation of nonproteogenic amino acids increased the peptides’ half-life towards enzymatic degradation while remaining nontoxic. Overall, our data convey key considerations for SAR using nonproteogenic amino acids, which provide analogs with better pharmacological properties.
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Conformational investigation of the structure–activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit
Proteins and peptides in nature are almost exclusively made from l -amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d -amino acids in biological processes have been revealed. Over 30 d -amino acid containing peptides (DAACPs) have been discovered in animals where at least one l -residue has been isomerized to the d -form via an enzyme-catalyzed process. In Aplysia californica , GdFFD and GdYFD (the lower-case letter “d” indicates a d -amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d -residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand–receptor interactions in the absence of high-resolution structural data.
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- Award ID(s):
- 1716956
- NSF-PAR ID:
- 10105973
- Date Published:
- Journal Name:
- Physical Chemistry Chemical Physics
- Volume:
- 20
- Issue:
- 34
- ISSN:
- 1463-9076
- Page Range / eLocation ID:
- 22047 to 22057
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C8CP03661F
