Biodynamers as biocompatible, fluorescent, and dynamic polyhistidine-based chelators for diagnosis of Cu (II) homeostasis deregulation Lena Zeroug-Metz 1 , Justine Bassil 2 and Sangeun Lee 1,2 1 Pharmaceutical Materials and Processing, Department of Pharmacy, Saarland University, 66123 Saarbrücken, Germany 2 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) – Helmholtz Centre for Infection Research (HZI), Campus E 8.1, 66123 Saarbrücken, Germany As an essential trace element, Copper is an important factor for numerous functions in the body, such as electron transfer for cellular respiration and redox regulation. [1,2] Although only trace amounts of the metal are needed, deregulation in homeostasis can lead to pathological manifestation of neurological diseases such as Menkes disease or Morbus Wilson. [2] Monitoring Copper (II) levels selectively, therefore, is crucial. [3] However, the lack of water solubility, biocompatibility as well as a confirmed biodegradability of Cu (II)sensors can set clear limitations for biological applications. [2] In our research, we focus on proteoid carbazole-derived biodynamers, which mimic biological biopolymers such as polysaccharides and peptides. Biodynamers are highly water-soluble, biocompatible and degradable polymers, containing dynamic covalent bonds (DCB). [4] Via polycondensation under mildly acidic conditions, amino acid hydrazides and carbazol derivatives form reversible acylhydrazone - and imine bonds, leading to the self-folding in to a nanorod. [4] For fluorescent ion sensors to work effectively, a sensitive ion-recognition site that can induce a clear change in fluorescence when chelated to a specific central ion and thereby influence the fluorophore, is needed [5] .
The efficacy of carbazole derivates as fluorophore, containing oxygen and nitrogen groups as ionophores, has already been confirmed to be effective for coordination of bivalent metal cations in previous studies. [5] Assessing our fluorescent biodynamers as effective biocompatible ion sensor, we started by introducing physiologically important metal ions in order to explore ion-sensitivity and selectivity. First, we evaluated the variation in fluorescence (FL) among various biodynamers derived from different amino acids upon the addition of Cu (II) and other metal ions (Fig 1, Graph A). Focusing on the most promising results, we were able to confirm a selective Cu (II) dependent fluorescence depletion of polyhistidine-derived biodynamers (HisBD) in neutral aqueous medium (Fig 1, Graph B). The introduction of 1:1 eq. Cu (II) (50 µM) to HisBD resulted in a depletion of up to 88% of the initial relative fluorescence. Further to this, adding 1:8 eq. Cu(II)) (12.5 µM) already leads to a relative FL-depletion of 68 % (Fig. 1, Graph C).
Concluding our results, our novel polyhistidine-derived biodynamers (HisBD) show high Cu (II) selectivity via FL- depletion caused by BD-Ion coordination due to its functional groups, sidechains, and nanostructure formation. In perspective, our biopolymer is highly promising for application as smart, selective, and sensitive water-soluble Cu(II)biosensor with high biocompatibility. References
1. C. Ayudhya et al.,Biol Trace Elem Res. 2010 , 134:352–363 2. A. Lucena-Valera et al., World J Hepatol. 2021 , 13(6), 634–649. 3. H. Fang et al., Chem. Commun. 2018 , DOI:10.1039/C8CC00008E. 4. S. Lee et al., Mater.Chem. Front. 2020 , 4(3), 905–909 5. Ye et al., Chem Heterocycl Compd. 2018 , 54(2), 146–152
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