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Engineering Strategies for Oral Therapeutic Enzymes to Enhance Their Stability and Activity

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Therapeutic Enzymes: Function and Clinical Implications

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1148))

Abstract

Oral application of therapeutic enzymes is a promising and non-invasive administration that improves patient compliance. However, the gastrointestinal tract poses several challenges to the oral delivery of proteins, including harsh pH conditions and digestive proteases. A promising way to stabilise enzymes during their gastrointestinal route is by modification with polymers that can provide both steric shielding and selective interaction in different digestive compartments. We give an overview of modification technologies for oral enzymes ranging from functionalisation of native proteins, to site-specific mutation and protein-polymer engineering. We specifically focus on enzymes that are active directly in the gastrointestinal lumen and not systemically absorbed. In addition, we discuss examples of microparticle and nanoparticle encapsulated enzymes for improved oral delivery. The modification of orally administered enzymes offers a broad chemical variability and may be a promising tool for enhancing their gastrointestinal stability.

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Abbreviations

2-BIBB:

2-bromoisobutyryl bromide

AP:

Alkaline phosphatase

ATRP:

Atom transfer radical polymerization

BCA:

Bicinchoninic acid

BTpNA:

Benzoyl-l-tyrosine p-nitroanilide

CAP:

Cellulose acetate phthalate

CD:

Circular dichroism

CLSM:

Confocal laser scanning microscopy

CM:

Carboxymethyl

CT:

α1-antichymotrypsin

DLS:

Dynamic light scattering

DSC:

Differential scanning calorimetry

EDC:

1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide

FDA:

Food and drug administration USA

FITC-BSA:

Fluorescein isothiocyanate conjugate - bovine serum albumin

FTIR:

Fourier-transform infrared spectroscopy

GI:

Gastrointestinal

GPC:

Gel permeation chromatography

H/D:

Hydrogen/deuterium

HA:

Hyaluronic acid

HAP:

Hydroxyapatite

HPLC:

High performance liquid chromatography

HPMCP:

Hydroxyl propyl methyl cellulose phthalate

HRP:

Horseradish peroxidase

LC-MS:

Liquid chromatography–mass spectrometry

LCST:

Lower critical solution temperature

MALDI-TOF-MS:

Matrix assisted laser desorption ionization time-of-flight mass spectrometry

MP:

Microparticle

mPEG2-NHS:

Branched PEG N-hydroxysuccinimide

MW:

Molecular weight

NCC:

Nanoceramic cores

NHS:

N-hydroxysuccinimide

NHS-Br:

N-Hydroxysuccinimide-bromide

NMR:

Nuclear magnetic resonance

o-NP:

Ortho-nitrophenol

o-NPG:

Ortho-nitrophenyl-β-galactoside

PAMAM:

Poly(amidoamine)

PBPE:

Polymer-based protein engineering

pCBAm:

Poly (carboxybetaine acrylamide)

PDMAEMA:

Poly(2-(dimethylamino)ethyl methacrylate)

pDMAPS:

Poly[N,N′-dimethyl (methacryloylethyl) ammonium propane sulfonate]

PEG:

Polyethylene glycol

PEP:

Proline-specific endopeptidase

pNIPAm:

Poly (N-isopropylacry-lamide)

pOEGMA:

Poly(oligoethylene glycol monomethylether methacry-late)

pQA:

Poly-(quarternary ammonium methacrylate

pSMA:

Poly-(sulfonate methac-rylate)

RT:

Room temperature

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

SEC:

Size exclusion chromatography

SEM:

Scanning electron microscopy

SGC:

Simulated gastric conditions

SGF:

Simulated gastric fluid

SIC:

Simulated intestinal tract conditions

SIF:

Simulated intestinal fluid

Suc-Ala-Ala-Pro-Phe-pNA:

N-succinyl-L-alanyl-L-alanyl-L-prolyl-L-phenyla-lanine4-nitroanilide

TEM:

Transmission electron microscopy

Tm :

Denaturation midpoint

TM-AvPAL:

Triple mutant-Anabaena variabilis phenylalanine ammonia lyase

TNBSA:

2,4,6-trinitrobenzene sulfonic acid

UCST:

Upper critical solution temperature

UV-vis:

Ultraviolet-visible α1-anti

α-CT:

α-chymotrypsin

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Authors and Affiliations

  1. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Biogenic Nanotherapeutics Group (BION), Saarbrücken, Germany

    Philipp Lapuhs & Gregor Fuhrmann

  2. Department of Pharmacy, Saarland University, Saarbrücken, Germany

    Gregor Fuhrmann

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  1. Philipp Lapuhs
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Correspondence to Gregor Fuhrmann .

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  1. Department of Biotechnology, Agricultural University of Athens, Athens, Greece

    Nikolaos Labrou

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Lapuhs, P., Fuhrmann, G. (2019). Engineering Strategies for Oral Therapeutic Enzymes to Enhance Their Stability and Activity. In: Labrou, N. (eds) Therapeutic Enzymes: Function and Clinical Implications. Advances in Experimental Medicine and Biology, vol 1148. Springer, Singapore. https://doi.org/10.1007/978-981-13-7709-9_8

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