Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2

Xie, Yuanchao; Yin, Wanchao; Zhang, Y; Shang, Weijuan; Wang, Zhen; Luan, Xiaodong; Tian, Guanghui; Aisa, Haji Akber; Xu, Yechun; Xiao, Gengfu; Li, Jia; Jiang, Hualiang; Zhang, Shuyang; Zhang, Leike; Xu, H. Eric; Shen, Jingshan

doi:10.1038/s41422-021-00570-1

Cited by 80 publications

(93 citation statements)

References 7 publications

(5 reference statements)

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“…RDV is the first FDA-approved drug for the treatment of COVID-19, which is also a nucleoside analog. Compared with RDV, VV116 exhibits better in vitro antiviral activity and selectivity [ 14 ]. In addition, VV116 could be administered orally and has favorable oral bioavailability, that is more convenient for COVID-19 patients than intravenous administration of RDV.…”

Section: Discussionmentioning

confidence: 99%

“…These kinds of antiviral drugs are characterized with high efficacy and low incidence of viral resistance [ 12 , 13 ]. Recently, we reported a promising oral drug candidate VV116 (JT001) for treating SARS-CoV-2 infection by a comprehensive preclinical study [ 14 ]. VV116 is a deuterated, tri-isobutyrate ester prodrug of the RDV parent nucleoside, and is rapidly metabolized into the parent nucleoside (116-N1) in the body.…”

Section: Introductionmentioning

confidence: 99%

“…VV116 showed potent activity against a panel of SARS-CoV-2 variants (alpha, beta, delta, and omicron) and excellent therapeutic efficacy in the mice model. This prodrug was endowed with significantly improved oral absorption and a favorable tissue distribution profile, circumventing the liver-targeting issue of the phosphoramidate prodrugs [ 14 , 15 ].

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Section: Introductionmentioning

confidence: 99%

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Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects

Wang

Zhang

et al. 2022

Acta Pharmacol Sin

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VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fig.…”

Section: Introductionmentioning

confidence: 99%

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Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects

Wang

Zhang

et al. 2022

Acta Pharmacol Sin

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“…2b ), which may cause the delayed chain termination of Remdesivir on RdRp. Because Remdesivir is intravenously administered nucleotide prodrug that is inconvenient to patients, VV116, an orally available Remdesivir derivative, was developed and showed excellent efficacy in inhibiting SARS-CoV-2 replication in cell-based and animal models [ 64 ] (Fig. 2b ).…”

Section: The Structures Of Rna-dependent Rna Polymerase and Replication-transcription Complexmentioning

confidence: 99%

Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19

Yin

Jiang

et al. 2022

Acta Pharmacol Sin

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and persistently threatens to humanity. With tireless efforts from scientists around the world, understanding of the biology of coronavirus has been greatly enhanced over the past 2 years. Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19. In this review, we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed. We present the examples of structure-based design of Pfizer’s novel anti-SARS-CoV-2 drug PF-07321332 (Paxlovid), Merck’s nucleotide inhibitor molnupiravir (Lagevrio), and VV116, an oral drug candidate for COVID-19. These examples highlight the importance of structure in drug discovery to combat COVID-19. We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies.

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“…Previous studies demonstrated that the Delta variant decreased the effectiveness of vaccines and increased the breakthrough infection rates [ 19 , 20 ]. Many researchers have focused on developing anti-SARS-CoV-2 drugs and found some potential drugs, such as Azvudine [ 21 ], Molnupiravir [ 22 ], Paxlovid, and antibodies [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Structural Comparison and Drug Screening of Spike Proteins of Ten SARS-CoV-2 Variants

et al. 2022

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SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has evolved many variants with stronger infectivity and immune evasion than the original strain, including Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Iota, Lambda, and 21H strains. Amino acid mutations are enriched in the spike protein of SARS-CoV-2, which plays a crucial role in cell infection. However, the impact of these mutations on protein structure and function is unclear. Understanding the pathophysiology and pandemic features of these SARS-CoV-2 variants requires knowledge of the spike protein structures. Here, we obtained the spike protein structures of 10 main globally endemic SARS-CoV-2 strains using AlphaFold2. The clustering analysis based on structural similarity revealed the unique features of the mainly pandemic SARS-CoV-2 Delta variants, indicating that structural clusters can reflect the current characteristics of the epidemic more accurately than those based on the protein sequence. The analysis of the binding affinities of ACE2-RBD, antibody-NTD, and antibody-RBD complexes in the different variants revealed that the recognition of antibodies against S1 NTD and RBD was decreased in the variants, especially the Delta variant compared with the original strain, which may induce the immune evasion of SARS-CoV-2 variants. Furthermore, by virtual screening the ZINC database against a high-accuracy predicted structure of Delta spike protein and experimental validation, we identified multiple compounds that target S1 NTD and RBD, which might contribute towards the development of clinical anti-SARS-CoV-2 medicines. Our findings provided a basic foundation for future in vitro and in vivo investigations that might speed up the development of potential therapies for the SARS-CoV-2 variants.

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Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2

Cited by 80 publications

References 7 publications

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects

Structure genomics of SARS-CoV-2 and its Omicron variant: drug design templates for COVID-19

Structural Comparison and Drug Screening of Spike Proteins of Ten SARS-CoV-2 Variants

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