Anti‐VEGF DNA‐based aptamers in cancer therapeutics and diagnostics

Riccardi, Claudia; Napolitano, Ettore; Platella, Chiara; Musumeci, Domenica; Melone, Mariarosa Anna Beatrice; Montesarchio, Daniela

doi:10.1002/med.21737

Cited by 40 publications

(39 citation statements)

References 251 publications

(621 reference statements)

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“…The detailed results of clinical trials involving antibodies, proteins, and aptamers ligands, as well as gene therapy of VEGF-A, are also outside the scope of this review. The reader is referred to recent articles on these topics [36,44,57]. The novelty of the present review is the focus on the binding modes and the structures of ligands with high affinity and specificity for VEGFs, for which robust information is available, i.e., X-ray crystallography or NMR data.…”

Section: Scope Of the Reviewmentioning

confidence: 99%

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

Gaucher

Vidal

et al. 2021

Molecules

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The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.

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Section: Scope Of the Reviewmentioning

confidence: 99%

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

Gaucher

Vidal

et al. 2021

Molecules

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“…Due to the high clinical importance of VEGF, a number of anti-VEGF nucleic acid-based aptamers has been identified by SELEX and also suitably engineered to produce homodimeric or multimeric forms [ 209 ], also taking into account the homodimeric nature of VEGF 165 [ 200 , 201 ].…”

Section: Anticancer Aptamersmentioning

confidence: 99%

“…Besides DNA-based aptamers with stem-loop structures, also high affinity G-rich oligonucleotides were fished out against VEGF 165 by SELEX [ 209 ].…”

Section: Anticancer Aptamersmentioning

confidence: 99%

Dimeric and Multimeric DNA Aptamers for Highly Effective Protein Recognition

et al. 2020

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Multivalent interactions frequently occur in biological systems and typically provide higher binding affinity and selectivity in target recognition than when only monovalent interactions are operative. Thus, taking inspiration by nature, bivalent or multivalent nucleic acid aptamers recognizing a specific biological target have been extensively studied in the last decades. Indeed, oligonucleotide-based aptamers are suitable building blocks for the development of highly efficient multivalent systems since they can be easily modified and assembled exploiting proper connecting linkers of different nature. Thus, substantial research efforts have been put in the construction of dimeric/multimeric versions of effective aptamers with various degrees of success in target binding affinity or therapeutic activity enhancement. The present review summarizes recent advances in the design and development of dimeric and multimeric DNA-based aptamers, including those forming G-quadruplex (G4) structures, recognizing different key proteins in relevant pathological processes. Most of the designed constructs have shown improved performance in terms of binding affinity or therapeutic activity as anti-inflammatory, antiviral, anticoagulant, and anticancer agents and their number is certainly bound to grow in the next future.

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“…Starting from large pools of random-sequence oligonucleotides, aptamers are generally identified through a reiterative fishing procedure based on affinity chromatography, known as SELEX (systematic evolution of ligands by exponential enrichment) [4][5][6][7][8]. Notably, aptamers exhibit several advantages compared to antibodies [1,2], and, for this reason, have gained interest as agents of choice in both diagnostic [9][10][11] and therapeutic [12][13][14][15][16][17] applications. However, the biomedical use of aptamers still proceeds slowly; just a few candidates have entered clinical trials [14,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Charge-Transfer Interactions Stabilize G-Quadruplex-Forming Thrombin Binding Aptamers and Can Improve Their Anticoagulant Activity

Carvasal

Riccardi

Krauss

et al. 2021

IJMS

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In the search for optimized thrombin binding aptamers (TBAs), we herein describe the synthesis of a library of TBA analogues obtained by end-functionalization with the electron-rich 1,5-dialkoxy naphthalene (DAN) and the electron-deficient 1,8,4,5-naphthalenetetra-carboxylic diimide (NDI) moieties. Indeed, when these G-rich oligonucleotides were folded into the peculiar TBA G-quadruplex (G4) structure, effective donor–acceptor charge transfer interactions between the DAN and NDI residues attached to the extremities of the sequence were induced, providing pseudo-cyclic structures. Alternatively, insertion of NDI groups at both extremities produced TBA analogues stabilized by π–π stacking interactions. All the doubly-modified TBAs were characterized by different biophysical techniques and compared with the analogues carrying only the DAN or NDI residue and unmodified TBA. These modified TBAs exhibited higher nuclease resistance, and their G4 structures were markedly stabilized, as evidenced by increased Tm values compared to TBA. These favorable properties were also associated with improved anticoagulant activity for one DAN/NDI-modified TBA, and for one NDI/NDI-modified TBA. Our results indicated that TBA pseudo-cyclic structuring by ad hoc designed end-functionalization represents an efficient approach to improve the aptamer features, while pre-organizing and stabilizing the G4 structure but allowing sufficient flexibility to the aptamer folding, which is necessary for optimal thrombin recognition.

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Anti‐VEGF DNA‐based aptamers in cancer therapeutics and diagnostics

Cited by 40 publications

References 251 publications

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

Dimeric and Multimeric DNA Aptamers for Highly Effective Protein Recognition

Charge-Transfer Interactions Stabilize G-Quadruplex-Forming Thrombin Binding Aptamers and Can Improve Their Anticoagulant Activity

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