Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin.
Article Details
- CitationCopy to clipboard
Schneider EK, Huang JX, Carbone V, Han M, Zhu Y, Nang S, Khoo KK, Mak J, Cooper MA, Li J, Velkov T
Plasma Protein Binding Structure-Activity Relationships Related to the N-Terminus of Daptomycin.
ACS Infect Dis. 2017 Mar 10;3(3):249-258. doi: 10.1021/acsinfecdis.7b00015. Epub 2017 Feb 10.
- PubMed ID
- 28142234 [ View in PubMed]
- Abstract
Daptomycin is a lipopeptide antibiotic that is highly bound to plasma proteins. To date, the plasma components and structure-activity relationships responsible for the plasma protein binding profile of daptomycin remain uncharacterized. In the present study we have employed a surface plasmon resonance assay together with molecular docking techniques to investigate the plasma protein binding structure-activity relationships related to the N-terminal fatty acyl of daptomycin. Three compounds were investigated: (1) native daptomycin, which displays an N-terminal n-decanoyl fatty acid side chain, and two analogues with modifications to the N-terminal fatty acyl chain; (2) des-acyl daptomycin; and (3) acetyl-daptomycin. The surface plasmon resonance (SPR) data showed that the binding profile of native daptomycin was in the rank order human serum albumin (HSA) >> alpha-1-antitrypsin > low-density lipoprotein >/= hemoglobin > sex hormone binding globulin > alpha-1-acid-glycoprotein (AGP) > hemopexin > fibrinogen > alpha-2-macroglobulin > beta2-microglobulin > high-density lipoprotein > fibronectin > haptoglobulin > transferrin > immunoglobulin G. Notably, binding to fatty acid free HSA was greater than binding to nondelipidated HSA. SPR and ultrafiltration studies also indicated that physiological concentrations of calcium increase binding of daptomycin and acetyl-daptomycin to HSA and AGP. A molecular model of the daptomycin-human serum albumin A complex is presented that illustrates the pivotal role of the N-terminal fatty acyl chain of daptomycin for binding to drug site 1 of HSA. In proof-of-concept, the capacity of physiological cocktails of the identified plasma proteins to inhibit the antibacterial activity of daptomycin was assessed with in vitro microbiological assays. We show that HSA, alpha-1-antitrypsin, low-density lipoprotein, sex hormone binding globulin, alpha-1-acid-glycoprotein, and hemopexin are responsible for the majority of the sequestering activity in human plasma. The findings are relevant to medicinal chemistry programs focused on the development of next-generation daptomycin lipopeptides. Tailored modifications to the N-terminal fatty acyl domain of the daptomycin molecule should yield novel daptomycin lipopeptides with more ideal plasma protein binding profiles to increase the levels of active (free) drug in plasma and improved in vivo activity.
DrugBank Data that Cites this Article
- Drugs
- Drug Carriers
Drug Carrier Kind Organism Pharmacological Action Actions Daptomycin Alpha-1-acid glycoprotein 1 Protein Humans NoBinderDetails Daptomycin Alpha-1-antitrypsin Protein Humans NoBinderDetails Daptomycin Hemopexin Protein Humans NoBinderDetails Daptomycin Low-density lipoprotein receptor Protein Humans NoBinderDetails Daptomycin Serum albumin Protein Humans NoBinderDetails Daptomycin Sex hormone-binding globulin Protein Humans NoBinderDetails