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Review
.2022 Jan 27;27(3):850.
doi: 10.3390/molecules27030850.

Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary

Affiliations
Review

Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary

Shujing Xu et al. Molecules..

Abstract

Viral infections pose a persistent threat to human health. The relentless epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health problem, with millions of infections and fatalities so far. Traditional approaches such as random screening and optimization of lead compounds by organic synthesis have become extremely resource- and time-consuming. Various modern innovative methods or integrated paradigms are now being applied to drug discovery for significant resistance in order to simplify the drug process. This review provides an overview of newly emerging antiviral strategies, including proteolysis targeting chimera (PROTAC), ribonuclease targeting chimera (RIBOTAC), targeted covalent inhibitors, topology-matching design and antiviral drug delivery system. This article is dedicated to Prof. Dr. Erik De Clercq, an internationally renowned expert in the antiviral drug research field, on the occasion of his 80th anniversary.

Keywords: antiviral drugs; drug design; medicinal chemistry strategies; viruses.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Newly emerging strategies in antiviral drug discovery.
Figure 2
Figure 2
Chemical structures and inhibitory activities of telaprevir (1) and the degrader derivative DGY-08-097 (2) [16].
Figure 3
Figure 3
Chemical structures of C5 (3) and C5-RIBOTAC (4, the heterocyclic recruiter of RNase L is shown in orange) and schematic of C5-RIBOTAC degradation of the SARS-CoV-2 RNA [20].
Figure 4
Figure 4
(A) Chemical structure of5 and crystal structures of Y181C RT in complex with5 (PDB code: 5VQX);5 forms a covalent bond with the sulfhydryl group of Cys181. (B) The same as A but with Y181C:6 (PDB code: 5VQV) [24]. The figures were generated by PyMol.
Figure 5
Figure 5
(A) Chemical structure of7 and the schematic rendering of the active site with dashed lines represented as hydrogen bonds with key residues and curved lines to show S1 and S2 binding pockets [25]; (B) chemical structures of8 and9; inhibitory activities against SARS-CoV-2 3CLPro(IC50) and in vitro inhibition of 3CLPro(EC50) [26].
Figure 6
Figure 6
(A) Proposed binding patterns between nano-inhibitor and IAV particles [29]; (B) proposed binding patterns between spiky nanoparticle-based inhibitor and IAV particles [30]; (C) proposed binding patterns between IAV and the heteromultivalent nanobowl (Hetero-MNB), where sialic acid and zanamivir bind to HA and NA, respectively, and the bowl shape facilitating the capping to the surface of the virus particle [31].
Figure 7
Figure 7
The discovery of ABT and inhibitory potency against a set of HIV-1 subtypes [34].
Figure 8
Figure 8
Chemical structure of zanamivir–cholesterol conjugate (12) [38].
See this image and copyright information in PMC

References

    1. De Clercq E. Antivirals: Past, present and future. Biochem. Pharmacol. 2013;85:727–744. doi: 10.1016/j.bcp.2012.12.011. - DOI - PubMed
    1. De Clercq E. Fifty Years in Search of Selective Antiviral Drugs. J. Med. Chem. 2019;62:7322–7339. doi: 10.1021/acs.jmedchem.9b00175. - DOI - PubMed
    1. De Clercq E. Antivirals and antiviral strategies. Nat. Rev. Microbiol. 2004;2:704–720. doi: 10.1038/nrmicro975. - DOI - PMC - PubMed
    1. Meyer H., Ehmann R., Smith G.L. Smallpox in the Post-Eradication Era. Viruses. 2020;12:138. doi: 10.3390/v12020138. - DOI - PMC - PubMed
    1. Trilla A., Trilla G., Daer C. The 1918 “Spanish flu” in Spain. Clin. Infect. Dis. 2008;47:668–673. doi: 10.1086/590567. - DOI - PubMed

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