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An intact C-terminal end of albumin is required for its long half-life in humans.

ABSTRACT: Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with this, a short half-life of only 3.5 days was measured for cleaved albumin lacking L585 in a patient with acute pancreatitis. Thus, we reveal the structural requirement of an intact C-terminal end of albumin for a long plasma half-life, which has implications for design of albumin-based therapeutics.

SUBMITTER: Nilsen J

PROVIDER: S-EPMC7171077 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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An intact C-terminal end of albumin is required for its long half-life in humans.

Nilsen Jeannette J Trabjerg Esben E Grevys Algirdas A Azevedo Claudia C Brennan Stephen O SO Stensland Maria M Wilson John J Sand Kine Marita Knudsen KMK Bern Malin M Dalhus Bjørn B Roopenian Derry C DC Sandlie Inger I Rand Kasper Dyrberg KD Andersen Jan Terje JT

Communications biology 20200420 1

Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. ...[more]

PMID: 32313072

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Project description:According to the WHO, artemisinin-based combination therapies (ACTs) have been integral to the recent reduction in deaths due to Plasmodium falciparum malaria. ACT-resistant strains are an emerging problem and have evolved altered developmental stages, reducing exposure of the most susceptible stages to artemisinin drugs in popular ACTs. Lipophilicity, log K ow, is a guide in understanding and predicting pharmacokinetic properties such as terminal half-life which alters drug exposure. Consistent log K ow values are not necessarily available for artemisinin derivatives designed to extend terminal half-life, increase bioavailability, and reduce neurotoxicity. For other drugs used in ACTs, an assortment of experimental and computational log K ow values are available in the literature and in some cases, do not account for subtle but important differences between closely related structures such as between diastereomers. Quantum chemical methods such as density functional theory (DFT) used with an implicit solvent model allow for consistent comparison of physical properties including log K ow and distinguish between closely related structures. To this end, DFT, B3LYP/6-31G(d), with an implicit solvent model (SMD) was used to compute ΔG ow o and ΔG vow o for 1-octanol-water and olive oil-water partitions, respectively, for 21 antimalarial drugs: 12 artemisinin-based, 4 4-aminoquinolines and structurally similar pyronaridine, and 4 amino alcohols. The computed ΔG ow o was close to ΔG ow o calculated from experimental log K ow values from the literature where available, with a mean signed error of 2.3 kJ/mol and mean unsigned error of 3.7 kJ/mol. The results allow assignment of log K ow for α-and β-diastereomers of arteether, and prediction of log K ow for β-DHA and five experimental drugs. Linear least square analysis of log K ow and log K vow versus terminal elimination half-life showed strong linear relationships, once the data points for the 4-aminoquinoline drugs, mefloquine and pyronaridine were found to follow their own linear relationship, which is consistent with their different plasma protein binding. The linear relationship between the computed log K vow and terminal elimination half-life was particularly strong, R 2 = 0.99 and F = 467, and can be interpreted in terms of a simple pharmacokinetic model. Terminal elimination half-life for β-DHA and four experimental artemisinin drugs were estimated based on this linear relationship between log K vow and terminal t 1/2. The computed log K ow and log K vow values for epimers α- and β-DHA and α and β-arteether provide physical data that may be helpful in understanding their different pharmacokinetics and activity based on their different molecular geometries. Relative solubility of quinine and quinidine are found to be sensitive to thermal corrections to enthalpy and to vibrational entropy and do not follow the general trend of longer terminal t 1/2 with greater predicted log K ow. Geometric relaxation of α- and β-DHA in solvent and inclusion of thermal correction for enthalpy and entropy results in correct prediction that α-DHA is favored in aqueous environments compared to β-DHA. Predictions made regarding experimental drugs have implications regarding their potential use in response to artemisinin drug-resistant strains.

Dataset Information

An intact C-terminal end of albumin is required for its long half-life in humans.

Publications

An intact C-terminal end of albumin is required for its long half-life in humans.

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