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Review
. 2021 Feb 9;26(4):923.
doi: 10.3390/molecules26040923.

Drug Discovery of Nucleos(t)ide Antiviral Agents: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Birthday

Guangdi Li  1   2 , Tingting Yue  2 , Pan Zhang  2 , Weijie Gu  3 , Ling-Jie Gao  3 , Li Tan  1
Affiliations
Review

Drug Discovery of Nucleos(t)ide Antiviral Agents: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Birthday

Guangdi Li et al. Molecules. .

Abstract

Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread®) and tenofovir alafenamide (Vemlidy®) against HIV and HBV infections and adefovir dipivoxil (Hepsera®) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex®) against HSV-1 and VZV infections and stavudine (Zerit®) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex®, Zelitrex®) against HSV and VZV and rabacfosadine (Tanovea®-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide®) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.

Keywords: HBV; HCMV; HCV; HIV; HSV; VZV; antiviral therapy; nucleoside analogue; nucleotide analogue.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Adenosine monophosphate (a), N-nucleoside and C-nucleoside (b), and six approved adenosine nucleos(t)ide analogues (c–h).
Figure 2
Figure 2
Thymidine and five approved thymidine nucleos(t)ide analogues: (a) idoxuridine, (b) trifluridine, (c) zidovudine, (d) telbivudine, and (e) sofosbuvir.
Figure 3
Figure 3
Thymidine and thymidine nucleoside analogues. Development from thymidine (a) to brivudine (b) and stavudine (c). A case of acute herpes zoster was treated by brivudine (d). In the first 3 days after symptom onset, a corticosteroid topical cream (mometasone furoate) offered no improvement. Based on the advice of our beloved professor Erik De Clercq, three once-daily tablets of brivudine (Zostex®) were subsequently used to cure the herpes zoster, and all crusts fell off 3 weeks later. Front and back views were taken before the brivudine treatment and 2 months after the treatment.
Figure 4
Figure 4
Guanosine and its nine approved analogues: (a) acyclovir, (b) valacyclovir, (c) rabacfosadine, (d) ganciclovir, (e) valganciclovir, (f) didanosine, (g) entecavir, (h) penciclovir, and (i) famciclovir.
Figure 5
Figure 5
Cytidine monophosphate (a) and four approved cytidine nucleos(t)ide analogues: (b) cidofovir, (c) lamivudine, (d) emtricitabine, and (e) zalcitabine.
See this image and copyright information in PMC

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