Allosteric inhibition of α-thrombin enzymatic activity with ultrasmall gold nanoparticles

Lira, André L.; Ferreira, Rodrigo S.; Torquato, Ricardo J.S.; Oliva, Maria Luiza Vilela; Schuck, Peter; Sousa, Alioscka A.

doi:10.1039/c8na00081f

Cited by 33 publications

(61 citation statements)

References 87 publications

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“…The lone sulfated benzofuran 26 displays a partial inhibition profile (ΔY = 75%), which presents the possibility of regulating the MMP-8 activity (ΔY = 20–80%), rather than knocking it out completely. Recently, small molecule regulation of soluble enzymes has been discovered and was found to offer beneficial properties [ 38 , 46 , 47 ]. Similarly, regulation of the MMP-8–NSGM 26 system may offer the benefit of retaining basal levels of the MMP-8 activity that is critical for optimal growth.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Morla

Desai

2020

Biomolecules

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Elevated matrix metalloproteinase-8 (MMP-8) activity contributes to the etiology of many diseases, including atherosclerosis, pulmonary fibrosis, and sepsis. Yet, very few small molecule inhibitors of MMP-8 have been identified. We reasoned that the synthetic non-sugar mimetics of glycosaminoglycans may inhibit MMP-8 because natural glycosaminoglycans are known to modulate the functions of various MMPs. The screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds led to the identification of only two scaffolds, including sulfated benzofurans and sulfated quinazolinones, as promising inhibitors of MMP-8. Interestingly, the sulfated quinazolinones displayed full antagonism of MMP-8 and sulfated benzofuran appeared to show partial antagonism. Of the two, sulfated quinazolinones exhibited a >10-fold selectivity for MMP-8 over MMP-9, a closely related metalloproteinase. Molecular modeling suggested the plausible occupancy of the S1′ pocket on MMP-8 as the distinguishing feature of the interaction. Overall, this work provides the first proof that the sulfated mimetics of glycosaminoglycans could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8.

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Section: Resultsmentioning

confidence: 99%

Discovery of Sulfated Small Molecule Inhibitors of Matrix Metalloproteinase-8

Morla

Desai

2020

Biomolecules

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“…However, the bivalent aptamer ThAD displayed much stronger inhibition of thrombin cleavage activity (pink curve), even stronger than argatroban of the same concentration (brown curve), a direct thrombin inhibitor for clinical treatment of thrombosis . Although ThAD gave sensitive attenuation for thrombin cleavage activity with a molar ratio of 1:1, a higher dose of ThAD did not show further in‐creased inhibition, Figure B, meaning that the binding of ThAD could only partially and indirectly inhibit thrombin cleavage activity due to the binding of ThA allosterically affecting the activity center, as was also observed in other published work . This inhibition is different from that due to the direct inhibitor argatroban that binds to the enzymatic activity center.…”

Section: Resultsmentioning

confidence: 99%

DNA‐Nanoscaffold‐Assisted Selection of Femtomolar Bivalent Human α‐Thrombin Aptamers with Potent Anticoagulant Activity

Zhou

Liu

et al. 2019

ChemBioChem

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Multivalent aptamers that interact with their target proteins through multiple sites exhibit much stronger binding strengths than their monovalent counterparts. In this work, we have designed a single‐stranded DNA (ssDNA) library (1015 molecules, each 145 nt) based on a predefined DNA nanostructure designed to present two random‐loop sites for bivalent aptamer evolution. From this library, a group of ultra‐strong bivalent aptamers against human α‐thrombin (with apparent KD values of ≈340 fm) were easily identified through a simple seven‐round conventional systematic evolution of ligands by exponential enrichment (SELEX) procedure. The dominant bivalent aptamers consist of two components, one binding to exosite I and the other to exosite II. The best of these bivalent aptamers show strong allosteric attenuation of the thrombin cleavage activity and also display an extremely potent anticoagulation effect in human plasma, demonstrating their great potential in therapeutic applications. The method developed here can easily be adapted to conventional SELEX techniques, opening a new route for fast selection of multivalent aptamers with superior binding affinity for other targets.

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“…Charged usGNPs, in particular, can bind with high affinity to regions of opposite charge on protein surfaces. 23,45,54,[60][61][62] This feature has been exploited in several basic-science studies aimed at the design and use of synthetic usGNPs for protein surface recognition and the modulation of protein structure and function (cf. Section 6.1).…”

Section: Size and Surface Chemistry Of Usgnps And Their Influence On Nanobio Interactionsmentioning

confidence: 99%

“…Their interactions with proteins, membranes, and other biological structures, known as nano-bio interactions, can, in principle, be controlled through a judicious choice of design parameters, such as core size and shape, surface chemistry, and core composition. Relative to their classical counterparts, usNPs retain features that make them comparable to drugs, 20,21 with the potential for target selectivity and binding specicity to regulate protein function, [22][23][24][25] broadening the possibilities offered by traditional small-molecule medicine. usNPs have been used in traditional and emerging areas of therapy and diagnosis, including biosensing, biolabeling, protein recognition, drug delivery, and cancer theranostics and radiotherapy.…”

Section: Introductionmentioning

confidence: 99%