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Review
. 2024 May 13;16(5):770.
doi: 10.3390/v16050770.

Integrin-Targeting Strategies for Adenovirus Gene Therapy

Glen R Nemerow  1
Affiliations
Review

Integrin-Targeting Strategies for Adenovirus Gene Therapy

Glen R Nemerow. Viruses. .

Abstract

Numerous human adenovirus (AdV) types are endowed with arginine-glycine-aspartic acid (RGD) sequences that enable them to recognize vitronectin-binding (αv) integrins. These RGD-binding cell receptors mediate AdV entry into host cells, a crucial early step in virus infection. Integrin interactions with adenoviruses not only initiate receptor-mediated endocytosis but also facilitate AdV capsid disassembly, a prerequisite for membrane penetration by AdV protein VI. This review discusses fundamental aspects of AdV-host interactions mediated by integrins. Recent efforts to re-engineer AdV vectors and non-viral nanoparticles to target αv integrins for bioimaging and the eradication of cancer cells will also be discussed.

Keywords: adenovirus; bioimaging; extracellular matrix proteins; fiber; integrins; nanoparticles; penton base.

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Conflict of interest statement

The author declares no conflicts of interest. The writing of the manuscript and the decision to publish prior data was solely that of the author.

Figures

Figure 1
Figure 1
Three-dimensional structure of integrin αvβ3. The inactive (bent) form of the integrin (without its bound RGD ligand) is shown as a ribbon diagram with the αv subunit in blue and the β3 subunit in red (A). The C-terminus of these subunits are inserted into the cell membrane, whereas the N-terminal domains are involved in ligand binding. The extended (active) form of the integrin is shown in (B) with the location of the bound RGD ligand indicated by an *. A surface rendering of the alpha subunit (red) and beta subunit (blue) with the bound cyclo-RGDF peptide (stick figure) in the interface between the αv and β3 subunits is shown in (C). Reprinted by permission from Hynes, 2002, Cell press [3].
Figure 2
Figure 2
Diagram of the αv integrin family and natural ligands. αv integrins comprise five different heterodimeric receptors within the larger family of 24 known integrin molecules [3]. The majority of αv integrins recognize extracellular (ECM) ligands such as vitronectin and fibronectin that contain an RGD sequence. These receptor–ligand interactions foster cell adhesion and cell migration, processes crucial for maintaining normal cell homeostasis.
Figure 3
Figure 3
Multimeric associations of AdV2 and Ad12 with integrin αvβ5. CryoEM image reconstruction of Ad2 (left) and Ad12-integrin αvβ5 (right). In (A), the virus–integrin complexes are viewed along their icosahedral 3-fold axis. The hexons of the Ad particles are depicted in blue, the integrin is in red, and the penton base is in gold. In (B), the penton–integrin complexes are shown in-side view with the N-terminus of the fiber shaft (left) shown in green. The scale bars are 100 Å. Reprinted by permission from Chiu et al. 1999, Wiley publications [23].
Figure 4
Figure 4
Design of fluorescent silver sulfide nanoparticles displaying RGD integrin-targeting sequences. Nanoparticles known as quantum dots (orange) of ~1–10 nm with distinct tunable light emission spectra from 500–1200 nm can be derivatized with multiple RGD peptides (outlined in grey oval) to target various integrins (ABIR; alpha beta integrin receptor) depicted in the membrane cartoon (lower left). These nanoparticles, when administered in mouse models, show preferential tumor accumulation over time (lower right panel). Reprinted with permission from Tang et al. copyright 2015, ACS publications [75].
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Grants and funding

This research received no external funding.