Enhanced nitric oxide production by macrophages treated with a cell-penetrating peptide conjugate

Arfatur Rahman; Macgregor A Matthews; Cameron J Nowell; David K Chalmers; Philip E Thompson; Sandra E Nicholson; Nicholas Barlow; Raymond S Norton

doi:10.1016/j.bioorg.2022.105763

Enhanced nitric oxide production by macrophages treated with a cell-penetrating peptide conjugate

Bioorg Chem. 2022 Jun:123:105763. doi: 10.1016/j.bioorg.2022.105763. Epub 2022 Mar 26.

Authors

Arfatur Rahman¹, Macgregor A Matthews¹, Cameron J Nowell², David K Chalmers¹, Philip E Thompson¹, Sandra E Nicholson³, Nicholas Barlow⁴, Raymond S Norton⁵

Affiliations

¹ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
² Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
³ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
⁴ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia. Electronic address: nicholas.barlow@monash.edu.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; ARC Centre for Fragment-Based Design, Monash University, Parkville, VIC 3052, Australia. Electronic address: ray.norton@monash.edu.

PMID: 35366581
DOI: 10.1016/j.bioorg.2022.105763

Abstract

The SPRY domain-containing SOCS box protein-2 (SPSB2) plays a critical role in the degradation of inducible nitric oxide synthase (iNOS) in macrophages. In this study, we have conjugated a peptide inhibitor of the iNOS-SPSB2 interaction with a cell-penetrating peptide (CPP) for delivery into macrophages, and confirmed its binding to SPSB2. We have assessed the uptake of a fluorophore-tagged analogue by RAW 264.7 and immortalised bone marrow derived macrophage (iBMDM) cell lines, and shown that the CPP-peptide conjugate enhanced NO production. The findings of this study will be useful in further refinement of CPP-peptide conjugates as leads in the development of new antibiotics that target the host innate immune response.

Keywords: Cell-penetrating peptide; Macrophage; Pathogen killing; SPSB; iNOS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell-Penetrating Peptides* / pharmacology
Macrophages / metabolism
Models, Molecular
Nitric Oxide Synthase Type II / metabolism
Nitric Oxide*

Substances

Cell-Penetrating Peptides
Nitric Oxide
Nitric Oxide Synthase Type II