Fluorinated Protein and Peptide Materials for Biomedical Applications

Abstract

Fluorination represents one of the most powerful modern design strategies to impart biomacromolecules with unique functionality, empowering them for widespread application in the biomedical realm. However, the properties of fluorinated protein materials remain unpredictable due to the heavy context-dependency of the surrounding atoms influenced by fluorine’s strong electron-withdrawing tendencies. This review aims to discern patterns and elucidate design principles governing the biochemical synthesis and rational installation of fluorine into protein and peptide sequences for diverse biomedical applications. Several case studies are presented to deconvolute the overgeneralized fluorous stabilization effect and critically examine the duplicitous nature of the resultant enhanced chemical and thermostability as it applies to use as biomimetic therapeutics, drug delivery vehicles, and bioimaging modalities.

Escherichia coliadapts metabolically to 6- and 7-fluoroindole, enabling proteome-wide fluorotryptophan substitution

“…[65] Fluorine-containing building blocks have been extensively used to investigate and modify proteins and their interactions. [66][67][68] However, the adaptation of living organisms represents a step forward in exploring and understanding the consequences of global fluorination. At this point, we would like to highlight the outstanding achievements of a cell to cope with the intricate and myriad consequences associated with the exchange of a hydrogen against a fluorine atom in an essential building block (after all more than 20000 Trp positions only in the proteome).…”

Protein-Engineered Fibers For Drug Encapsulation Traceable via 19F Magnetic Resonance

“…To create an ideal theranostic biomaterial, without compromising drug encapsulation, diagnostic imaging must be optimized for improved detection . One such method to improve this specificity is the incorporation of fluorine into biomaterials …”

“…7 One such method to improve this specificity is the incorporation of fluorine into biomaterials. 8 Since fluorine is largely absent from organisms, yet exists in 100% natural abundance, it is useful as a contrast agent due to its specific signal in 19 F MRS. 9 In light of this, many 19 F MRS materials have been developed for biomedical applications 10−14 such as MRI cell tracking 15,16 and tumor imaging 17,18 as well as monitoring tumor cell hypoxia 19 and proliferation. 20 These agents are often synthetically derived to create fluorine-based polymers 17,21−23 or nanoemulsions.…”

Decorating phenylalanine side-chains with triple labeled 13 C/ 19 F/ 2 H isotope patterns

“…Therefore, many reports from literature indicate only minor changes in protein structure upon incorporation of uorinated amino acids, although the characteristics and functions including stability, folding, dynamic properties and interactions can be signi cantly altered by uorine (Welte et al 2020). Fluorine substituents at aromatic sidechains reduce the negative electrostatic potential of the corresponding aryl π-system, thereby changing its nature in contributing to π-π, cation-π, or XH-π interactions (Monkovic et al 2022). Fluorine-19 is an exceptionally valuable nucleus to study large protein complexes with very high resolution by NMR.…”