Molecular analysis and therapeutic applications of human serum albumin-fatty acid interactions

Linciano, Sara; Moro, Giulia; Zorzi, Alessandro; Angelini, Alessandro

doi:10.1016/j.jconrel.2022.05.038

Cited by 32 publications

(21 citation statements)

References 77 publications

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“…Intramolecular and intermolecular hydrogen bond interactions were analyzed by PROFUNC, 53 LIGPLOT+, 54 and PYMOL software. 55 The Protein Data Bank (PDB) identification code for the hSA-HPFO-DA-Myr ternary complex is 7Z57.…”

Section: Isothermal Titration Calorimetrymentioning

confidence: 99%

“…The three-dimensional structures were generated and rendered using PYMOL. 55 tail that establish polar and nonpolar contacts with surrounding hSA residues.…”

Section: Crystal Structure Of Hsa In Complex With Hpfo-damentioning

confidence: 99%

“…The titration profiles are colored in light red and light blue for C6O4, red and blue for PFHxA, and dark red and dark blue for HPFO-DA; (c) difference in enthalpy (ΔH) of the HPFO-DA, C6O4,and PFHxA binding to hSA in absence of competitors (light gray), in the presence of ibuprofen (Ibu, salmon) or in the presence of warfarin (War, blue). The three-dimensional structure was generated and rendered using PYMOL 55.…”

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confidence: 99%

“…For visualization, only intermolecular polar interactions below 3.0 Å are shown. The three-dimensional structures were generated and rendered using PYMOL 55.…”

mentioning

confidence: 99%

“…The color intensity correlates with the number of the interactions, with numerous and few interactions shown as light and dark colors, respectively. The three-dimensional structures were generated and rendered using PYMOL 55.…”

mentioning

confidence: 99%

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Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds

Moro

Liberi

Vascon

et al. 2022

Chem. Res. Toxicol.

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The current trend dealing with the production of per-and polyfluoroalkyl substances (PFASs) involves the shifting toward branched short-chain fluorinated compounds known as new-generation PFASs. A key aspect to be clarified, to address the adverse health effects associated with the exposure to PFASs, is their binding mode to human serum albumin (hSA), the most abundant protein in plasma. In this study, we investigated the interaction between hSA and two representative branched shortchain PFASs, namely, HPFO-DA and C6O4. In-solution studies revealed that both compounds bind hSA with affinities and stoichiometries lower than that of the legacy long-chain perfluoroalkyl compound PFOA. Competition experiments using hSA-binding drugs with known site-selectivity revealed that both HPFO-DA and C6O4 bound to pockets located in subdomain IIIA. The crystal structure of hSA in complex with HPFO-DA unveiled the presence of two binding sites. The characterization and direct comparison of hSA interactions with new-generation PFASs may be key elements for the understanding of the toxicological impact of these compounds.

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Section: Isothermal Titration Calorimetrymentioning

confidence: 99%

“…The three-dimensional structures were generated and rendered using PYMOL. 55 tail that establish polar and nonpolar contacts with surrounding hSA residues.…”

Section: Crystal Structure Of Hsa In Complex With Hpfo-damentioning

confidence: 99%

mentioning

confidence: 99%

“…For visualization, only intermolecular polar interactions below 3.0 Å are shown. The three-dimensional structures were generated and rendered using PYMOL 55.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds

Moro

Liberi

Vascon

et al. 2022

Chem. Res. Toxicol.

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Computational Analysis of Interactions Between Drugs and Human Serum Albumin

Yildiz

2024

J of Molecular Recognition

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Drug molecules exist as complexed with serum proteins such as human serum albumin (HSA) and/or unbound free form in the blood circulation. Drugs can be effective only when they are free. Thus, it is important to understand aspects that are important for interaction between drugs and interacting proteins. In this study, interactions among 2990 FDA approved drugs and HSA were computational analyzed to unravel principles that are critical for drug‐HSA interactions. Docking results showed that drugs have higher affinity toward cavity‐1 (C1) than cavity‐2 (C2). A total of 1131 drug molecules have docking score greater than 60 while 768 molecules have docking score greater than 60 when they are docked in C2. In addition, three solvent channels have potential to direct solvent to C1 cavity while C2 does not have any effective channel. The post MD analyses demonstrated that drugs are making polar interactions with basic amino acids in the binding cavities. Verbscoside and ceftazidime both have stable low RMSD values throughout MD simulation with 2 Å on average in C1 cavity. The ligand RMSD shows less stability for verbscoside, which is around 4 Å when it is in complex with HSA in C1. The individual contribution of the residues K192, K196, R215, and R254 to ceftazidime are −1.92 ± 0.18, −3.09 ± 0.09, −2.17 ± 0.17, and − 2.32 ± 0.098, respectively. These residues contribute the binding energy of the verbscoside by −6.06 ± 0.08, −2.10 ± 0.06, and − 1.57 ± 0.03 kcal/mol individually in C1 cavity. C2 is making polar interactions with drug via R469, K472, and K488 residues and their contribution to the two drugs are −3.13 ± 0.21 kcal/mol for R469, −1.94 ± 0.18 kcal/mol for K472, and −1.96 ± 0.11 kcal/mol for K488 to total binding energy of ceftazidime. The binding energy of verbscoside is 57.17 ± 7.00 kcal/mol and Arg‐407 has the highest contribution this bind energy individually with −4.29 ± 0.12 kcal/mol. Drugs with hydrogen bond donor/acceptor chemical adducts such as verbscoside involve higher hydrogen bond formation in C1 pocket. Ceftazidime makes interaction with HSA toward hydrophobic residues, L384, L404, L487, and L488 in the C2 cavity.

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Crystal structure of human serum albumin in complex with megabody reveals unique human and murine cross‐reactive binding site

De Felice,

Romanyuk,

Chinellato

et al. 2024

Protein Science

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The pharmacokinetic properties of small biotherapeutics can be enhanced via conjugation to cross‐reactive albumin binding ligands in a process that improves their safety and accelerates testing through multiple pre‐clinical animal models. In this context, the small and stable heavy–chain‐only nanobody NbAlb1, capable of binding both human and murine albumin, has recently been successfully applied to improve the stability and prolong the in vivo plasma residence time of multiple small therapeutic candidates. Despite its clinical efficacy, the mechanism of cross‐reactivity of NbAlb1 between human and murine serum albumins has not yet been investigated. To unveil the molecular basis of such an interaction, we solved the crystal structure of human serum albumin in complex with NbAlb1. The structure was obtained by harnessing the unique features of a megabody chimeric protein, comprising NbAlb1 grafted onto a modified version of the circularly permutated and bacterial‐derived protein HopQ. This structure showed that NbAlb1 contacts a yet unexplored binding site located in the peripheral region of domain II that is conserved in both human and mouse serum albumin proteins. Furthermore, we show that the binding of NbAlb1 to both serum albumin proteins is retained even at acidic pH levels, thus explaining its extended in vivo half‐life. The elucidation of the molecular basis of NbAlb1 cross‐reactivity to human and murine albumins might guide the design of novel nanobodies with broader reactivity towards a larger panel of serum albumins, thus facilitating the pre‐clinical and clinical phases in humans.This article is protected by copyright. All rights reserved.

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Molecular analysis and therapeutic applications of human serum albumin-fatty acid interactions

Cited by 32 publications

References 77 publications

Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds

Investigation of the Interaction between Human Serum Albumin and Branched Short-Chain Perfluoroalkyl Compounds

Computational Analysis of Interactions Between Drugs and Human Serum Albumin

Crystal structure of human serum albumin in complex with megabody reveals unique human and murine cross‐reactive binding site

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