Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing

Ruiz, Francesc Xavier; Hoang, Anthony N.; Dilmore, Christopher R; DeStefano, Jeffrey J.; Arnold, Eddy

doi:10.1016/j.drudis.2022.02.016

Cited by 6 publications

(2 citation statements)

References 73 publications

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“…The largest IA is present in the structure of the complex of aptamer tRNA Gln var-AGGU bound to glutaminyl-tRNA synthetase (entry #9, PDB ID 1EXD) [48]. Large areas (IA > 2000 Å 2 ) are exhibited by two classes of aptamers: (i) DNA aptamers interacting with HIV-1 reverse transcriptase subunits (entries #59, 64-68, 80-83, 105-107, 110-114, and 126, PDB IDs 5D3G, 5HLF, 5HP1, 5HRO, 5I3U, 5I42, 5XN0, 5XN1, 5XN2, 6BHJ, 7OXQ, 7OZ2, 7OZ5, 7LRI, 7LRM, 7LRX, 7LRY, 7LSK, and 7Z2G) [79,83,84,92,93,108,109] (Figure 4b); (ii) RNA aptamers (riboswitches) targeting DNA-directed RNA polymerase subunits (entries #140-142, PDB IDs 8G4W, 8G7E, and 8G8Z) [118]. In all these structures, the aptamer is involved in interactions with more than one protein subunit.…”

Section: Characterization Of the Interfaces That Stabilize Protein-ap...mentioning

confidence: 99%

Structural Insights into Protein–Aptamer Recognitions Emerged from Experimental and Computational Studies

Troisi,

Balasco,

Autiero

et al. 2023

IJMS

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Aptamers are synthetic nucleic acids that are developed to target with high affinity and specificity chemical entities ranging from single ions to macromolecules and present a wide range of chemical and physical properties. Their ability to selectively bind proteins has made these compounds very attractive and versatile tools, in both basic and applied sciences, to such an extent that they are considered an appealing alternative to antibodies. Here, by exhaustively surveying the content of the Protein Data Bank (PDB), we review the structural aspects of the protein–aptamer recognition process. As a result of three decades of structural studies, we identified 144 PDB entries containing atomic-level information on protein–aptamer complexes. Interestingly, we found a remarkable increase in the number of determined structures in the last two years as a consequence of the effective application of the cryo-electron microscopy technique to these systems. In the present paper, particular attention is devoted to the articulated architectures that protein–aptamer complexes may exhibit. Moreover, the molecular mechanism of the binding process was analyzed by collecting all available information on the structural transitions that aptamers undergo, from their protein-unbound to the protein-bound state. The contribution of computational approaches in this area is also highlighted.

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Section: Characterization Of the Interfaces That Stabilize Protein-ap...mentioning

confidence: 99%

Structural Insights into Protein–Aptamer Recognitions Emerged from Experimental and Computational Studies

Troisi,

Balasco,

Autiero

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…These include the blockbuster sofosbuvir for treating chronic hepatitis C and molnupiravir as the first oral drug for the treatment of COVID-19 (Figure ). Many of them, including those containing unnatural l -ribose and 2-deoxy- l -ribose (e.g., telbivudine in Figure ), require the crucial N -glycosylation to connect riboses/2-deoxyriboses with nucleobases (i.e., purines and pyrimidines) through glycosidic linkages in the natural β-orientation. However, N -glycosylation of nucleobases poses a formidable challenge in carbohydrate chemistry due to multiple factors such as the poor nucleophilicity of nucleobases and the N9/N7 regioselectivity issue of purines .…”

Section: Introductionmentioning

confidence: 99%

Direct Synthesis of α- and β-2′-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation

Tang,

Zhou,

Wang

et al. 2024

J. Am. Chem. Soc.

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2′-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on β-2′-deoxynucleosides with the natural β-configuration. In fact, their isomeric α-2′-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both αand β-2′-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2′-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial Nglycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2′-deoxynucleoside with IC 50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its β-anomer exhibited no inhibition at 100 μM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

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Mechanisms of Resistance to Antiviral Agents

Shafer,

Boivin,

Howe

et al. 2023

ClinMicroNow

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Understanding the mechanisms of viral drug resistance is critical for clinical management of individuals receiving antiviral therapy, for developing new antiviral drugs, and for drug resistance surveillance. This chapter reviews the mechanisms of resistance to antiviral drugs used to treat infections by eight common viruses: herpes simplex, cytomegalovirus, varicella‐zoster virus, human immunodeficiency virus type 1, influenza A and B, hepatitis B, hepatitis C, and severe acute respiratory syndrome coronavirus 2. Drug‐resistant virus subpopulations may exist at low levels in clinical isolates or may arise only during drug exposure. The error‐prone polymerases in RNA viruses render the development of resistance more frequent than in DNA viruses. Drug‐resistant viruses are identified by in vitro passage experiments in which wild‐type viruses are cultured in increasing concentrations of an inhibitory drug and by ex vivo analysis of virus isolates obtained from individuals receiving antiviral therapy.

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Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing

Cited by 6 publications

References 73 publications

Structural Insights into Protein–Aptamer Recognitions Emerged from Experimental and Computational Studies

Structural Insights into Protein–Aptamer Recognitions Emerged from Experimental and Computational Studies

Direct Synthesis of α- and β-2′-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation

Mechanisms of Resistance to Antiviral Agents

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