| Title: | Unveiling the Importance of Amide Protons in CSP:ComD Interactions in Streptococcus pneumoniae |
| Author(s): | Koirala B; Phillips NR; Tal-Gan Y; |
| Address: | "Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, Nevada 89557, United States" |
| DOI: | 10.1021/acsmedchemlett.9b00038 |
| ISSN/ISBN: | 1948-5875 (Print) 1948-5875 (Electronic) 1948-5875 (Linking) |
| Abstract: | "Streptococcus pneumoniae is an opportunistic pathogen that can cause diseases ranging from mild respiratory infections to life-threatening conditions such as pneumonia, meningitis, and bacteremia. S. pneumoniae pathogenicity is dependent on the action of a 17-amino acid peptide pheromone, termed competence stimulating peptide (CSP) that controls the competence regulon, a quorum sensing (QS) circuit. Therefore, intercepting QS could have therapeutic implications in treating pneumococcal infections while avoiding emerging antimicrobial resistance. In this study, we set out to evaluate the impact of amide protons on CSP activity and metabolic stability through systematic N-methylation. Our results indicate that the majority of amide protons are critical for CSP activity, either through direct interactions with the cognate receptor or by stabilizing the bioactive conformation. Importantly, we identified several N-methyl CSP analogs, namely, CSP1(15)-N-Me-K6 and CSP1(15)-N-Me-F7, that retain their biological activity while exhibiting enhanced metabolic stability. These analogs are privileged scaffolds for the design of CSP-based QS modulators with drug-like properties" |
| Notes: | "PubMed-not-MEDLINEKoirala, Bimal Phillips, Naiya R Tal-Gan, Yftah eng P20 GM103440/GM/NIGMS NIH HHS/ R35 GM128651/GM/NIGMS NIH HHS/ 2019/06/22 ACS Med Chem Lett. 2019 Apr 30; 10(6):880-886. doi: 10.1021/acsmedchemlett.9b00038. eCollection 2019 Jun 13" |
