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Plasma protein binding structure-activity relationships related to the N-terminus of daptomycin

Schneider, Elena K., Huang, Johnny X., Carbone, Vincenzo, Han, Meiling, Zhu, Yan, Nang, Sue, Khoo, Keith K., Mak, Johnson, Cooper, Matthew A., Li, Jian and Velkov, Tony 2017, Plasma protein binding structure-activity relationships related to the N-terminus of daptomycin, ACS infectious diseases, vol. 3, no. 3, pp. 249-258, doi: 10.1021/acsinfecdis.7b00015.

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Title Plasma protein binding structure-activity relationships related to the N-terminus of daptomycin
Author(s) Schneider, Elena K.
Huang, Johnny X.
Carbone, Vincenzo
Han, Meiling
Zhu, Yan
Nang, Sue
Khoo, Keith K.
Mak, Johnson
Cooper, Matthew A.
Li, Jian
Velkov, Tony
Journal name ACS infectious diseases
Volume number 3
Issue number 3
Start page 249
End page 258
Total pages 10
Publisher ACS Publications
Place of publication Washington, D.C.
Publication date 2017
ISSN 2373-8227
Keyword(s) N-terminus
daptomycin
plasma protein binding
Summary 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) ≫ α-1-antitrypsin > low-density lipoprotein ≥ hemoglobin > sex hormone binding globulin > α-1-acid-glycoprotein (AGP) > hemopexin > fibrinogen > α-2-macroglobulin > β2-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, α-1-antitrypsin, low-density lipoprotein, sex hormone binding globulin, α-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.
Language eng
DOI 10.1021/acsinfecdis.7b00015
Field of Research 110802 Medical Infection Agents (incl Prions)
Socio Economic Objective 920109 Infectious Diseases
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Grant ID nhmrc 1121697
Copyright notice ©2017, American Chemical Society
Persistent URL http://hdl.handle.net/10536/DRO/DU:30093441

Document type: Journal Article
Collection: School of Medicine
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