Dataset Information

Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: In silico Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents.

ABSTRACT: A major challenge in drug delivery is to enhance the transport of drugs across biological barriers, such as the small intestine, the blood-brain barrier, and the blood-retinal/ocular barrier, and to effectively reach the site of action while minimizing the systemic impact. In recent years, piggybacking cell surface receptors have been considered a viable strategy for active drug delivery across the biological barriers. However, the ligands used to target drugs to plasma membrane receptors often have to compete against endogenous ligands, thereby limiting their binding to the cell surface and their transport across barriers. To address this problem, gambogic acid (GA) was identified as a noncompetitive ligand specific to the transferrin receptor (TfR), a receptor present on various barriers. However, the binding sites of the GA on TfR remain unknown, an essential step toward establishing structure-activity relationships. In silico binding site prediction tools, blind docking, and molecular docking simulation confirm that the GA binding site on the TfR is independent of the transferrin-bound iron binding sites. The GA-conjugated polyesters were processed into nanoparticles suitable for drug delivery applications that possess excellent storage stability under regulatory conditions. Traditionally, GA has been used as an anticancer compound that warrants safety assessment. The preliminary studies in healthy rodents on 10-repeated oral doses show no adverse effects. This work will generate paradigm shifting, new knowledge in the field of nanomedicines using unique noncompetitive nanosystems that do not compete with endogenous transferrin.

SUBMITTER: Arora M

PROVIDER: S-EPMC6705617 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: <i>In silico</i> Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents.

Arora M M Ganugula R R Kumar N N Kaur G G Kaur G G Pellois J-P JP Pellois J-P JP Garg P P Kumar M N V Ravi MNVR

ACS applied bio materials 20190704 8

A major challenge in drug delivery is to enhance the transport of drugs across biological barriers, such as the small intestine, the blood-brain barrier, and the blood-retinal/ocular barrier, and to effectively reach the site of action while minimizing the systemic impact. In recent years, piggybacking cell surface receptors have been considered a viable strategy for active drug delivery across the biological barriers. However, the ligands used to target drugs to plasma membrane receptors often ...[more]

PMID: 31440745

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Project description:Transferrin-binding protein B (TbpB) from Neisseria meningitidis binds human transferrin (hTf) at the surface of the bacterial cell as part of the iron uptake process. To identify hTf binding sites within the meningococcal TbpB, defined regions of the molecule were produced in Escherichia coli by a translational fusion expression system and the ability of the recombinant proteins (rTbpB) to bind peroxidase-conjugated hTf was characterized by Western blot and dot blot assays. Both the N-terminal domain (amino acids [aa] 2 to 351) and the C-terminal domain (aa 352 to 691) were able to bind hTf, and by a peptide spot synthesis approach, two and five hTf binding sites were identified in the N- and C-terminal domains, respectively. The hTf binding activity of three rTbpB deletion variants constructed within the central region (aa 346 to 543) highlighted the importance of a specific peptide (aa 377 to 394) in the ligand interaction. Taken together, the results indicated that the N- and C-terminal domains bound hTf approximately 10 and 1000 times less, respectively, than the full-length rTbpB (aa 2 to 691), while the central region (aa 346 to 543) had a binding avidity in the same order of magnitude as the C-terminal domain. In contrast with the hTf binding in the N-terminal domain, which was mediated by conformational epitopes, linear determinants seemed to be involved in the hTf binding in the C-terminal domain. The host specificity for transferrin appeared to be mediated by the N-terminal domain of the meningococcal rTbpB rather than the C-terminal domain, since we report that murine Tf binds to the C-terminal domain. Antisera raised to both N- and C-terminal domains were bactericidal for the parent strain, indicating that both domains are accessible at the bacterial surface. We have thus identified hTf binding sites within each domain of the TbpB from N. meningitidis and propose that the N- and C-terminal domains together contribute to the efficient binding of TbpB to hTf with their respective affinities and specificities for determinants of their ligand.

Dataset Information

Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: In silico Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents.

Publications

Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: <i>In silico</i> Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents.

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