Molecular mechanism of azvudine in the treatment of COVID-19 based on network pharmacology and molecular docking

Azvudine(FNC)is a nucleotide inhibitor with a wide antiviral drug.Azvudine was available for the treatment of HIV and corona virus disease(COVID-19)in 2019,but its efficacy and mechanism of action for the treatment of COVID-19 have not been evaluated.PharmMapper was used to predict 287 potentially relevant targets,and the OMIM and GeneCards databases yielded 2468 potential related targets.COVID-19 is linked to 72 FNC-related targets.Using gene ontology(GO)functional annotation and kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment,binding protein-protein interaction(PPI)networks and cytoHubba plug-ins,10 relevant signaling pathways(Lipid and atherosclerosis,Pathways in cancer,Coronavirus disease COVID-19,T cell receptor signaling pathway,and so on.)and 10 hub genes were identified.FNC was shown to interact with MMP9,ALB,AKT1,EGFR,HRAS,MAPK14,MAPK8,PPARG,RHOA and NOS3 via molecular docking.This work investigated the key routes and targets of FNC in the treatment of COVID-19,as well as the possible anti-COVID-19 and anti-tumor targets and related signaling pathways of FNC,which provided references for us to locate and explore effective COVID-19 medications.

Selectively T cell phosphorylation activation of azvudine in the thymus tissue with immune protection effect

Thymus is the important immune organ,responsible for T cell development and differentiation.The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors.Azvudine,also known as FNC,is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients.In this study,single-cell transcriptome,proteomics,and parallel reaction monitoring(PRM)were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus.The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC.Key enzymes involved in the FNC phosphorylation process,such as Dck,Cmpk1,and Nme2,were highly expressed in CD4+ T cells,CD8+ T cells,and DP(CD4+ CD8+)cells.Additionally,FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases,phosphoribosyl transferases,and deaminases,respectively.The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC,and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect.This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties,as an important factor during antiviral drug design.

Concomitant and sequential administration of nirmatrelvir-ritonavir and azvudine in patients with COVID-19 caused by the Omicron variant: Safety and efficacy

Background:This study assessed the safety and efficacy of nirmatrelvir-ritonavir(Paxlovid®)and azvudine when administered sequentially or concomitantly in patients with coronavirus 2019(COVID-19)caused by the Omicron variant.Methods:Ninety-three patients confirmed to be infected with the Omicron variant by nucleic acid detection were retrospectively investigated.Informa-tion was collected on general health status,medication,and adverse drug reactions(ADRs)according to whether nirmatrelvir-ritonavir and azvudine were administered sequentially or concomitantly.Data on times of onset,clinical manifestations,and outcomes of ADRs and on conversion to a nega-tive nucleic acid test were also recorded.Results:Possible ADRs were recorded in 41 patients(44.1%).There were 22 gastrointestinal reactions in 18 patients and 18 hematological abnormalities in 16 after sequential or concomitant treatment with nirmatrelvir-ritonavir and azvudine.Liver enzyme levels increased in nine cases and creatinine clearance decreased in two.Cases of atrial fibrillation(n=1),sleep disorder(n=2),rash(n=2),dizziness(n=1),and weakness(n=5)were also documented.Only vomiting,poor appetite,diarrhea,xerostomia,bitter taste,and rash were considered probable ADRs;others were thought to be possible ADRs.In all cases,the nucleic acid test did not turn negative after the first antiviral was applied.The nucleic acid test of 28 patients did not turn negative before discharge.The remaining 65 patients(69.9%)returned a negative nucleic acid test after receiving the second antiviral agent.Conclusions:Treatment with nirmatrelvir-ritonavir and azvudine is safe and effective whether administered sequentially or concomitantly in patients with COVID-19 caused by the Omicron variant.

Azvudine reduces the in-hospital mortality of COVID-19 patients:A retrospective cohort study

In our retrospective cohort study,we aim to explore whether Azvudine modifies the risk of death in COVID-19 patients.It was conducted on the medical records of patients,consecutively admitted for COVID-19 pneumonia to two hospitals in Chongqing,China.Based on Azvudine treatment exposure,the patients were divided into Azvudine group and non-Azvudine group.We used 1:2 ratio propensity score matching(PSM)in our study to adjust for confounding factors and differences between Azvudine and non-Azvudine groups.There were 1072 patients included in our original cohort.With 1:2 ratio PSM,the Azvudine group included 195 patients and non-Azvudine group included 390 patients.The results showed that Azvudine treatment was associated with improved in-hospital mortality in overall population(OR 0.375,95%CI 0.225-0.623,P<0.001),severe subgroup(OR 0.239,95%CI 0.107-0.535,P=0.001),critical subgroup(OR 0.091,95%CI 0.011-0.769,P=0.028)in matched cohort with univariate analysis.And there was a significantly lower in-hospital mortality in overall population(11%vs.24%,P<0.001),severe sub-group(10%vs.32%,P<0.001)and critical sub-group(5%vs.34%,P=0.017)in matched cohort.These results suggest Azvudine can reduce in-hospital mortality in overall COVID-19 patients,severe,and critical subgroup population.

A Nearly 20-Year Journey to Success of Azvudine for Antiviral Therapy

Modified nucleosides,particularly those with 4'-modifications,are significant nucleosides used in antiviral treatments.The drug discovery campaign of Azvudine starts from 2′-deoxynucleoside,followed by extensive modifications,such as introducing the 4’-position substitutions,a 2’-β-fluoro atom,and changing the nucleobases.Azvudine acts potently toward various HIV-1 strains by inhibiting HIV-1 reverse transcription and preventing Vif-induced A3G degradation,representing the first-in-class dual-acting antiviral agent.In July 2021,the NMPA conditionally approved Azvudine as an adjunct therapy for adult patients with high levels of HIV-1 virus load when combined with NRTIs or NNRTIs.Azvudine is capable of inhibiting SARS-CoV-2,as well as its variants,including Alpha,Beta,Delta,and Omicron.Clinical trials have revealed its real-world effectiveness among hospitalized severely or critically ill COVID-19 patients or those with pre-existing conditions.On July 25th,2022,the NMPA granted conditional authorization approving Azvudine as China's first domestic oral anti-COVID-19 agent.Generally,Azvudine at therapeutic doses is safe and well-tolerated in clinical settings.Azvudine got approval from the National Health Commission and National Administration of Traditional Chinese Medicine on August 9th to be used in the"Diagnosis and Treatment Program for Novel Coronavirus Pneumonia(Ninth Edition)"for treating common COVID-19 adult patients.On August 12th,2022,it was also approved by the National Healthcare Security Administration to be added to the list of medical reimbursements.Of note,the achievements related to Azvudine were indexed in the China Basic Research Development Report in Thirty-Five of 2022.Azvudine was also approved on January 5th,2023,to be used in the"Diagnosis and Treatment Program for Novel Coronavirus Pneumonia(Tenth Edition)"for treating COVID-19 patients.In February 2023,the Ministry of Health of the Russian Federation approved the usage of Azvudine among individuals infected with SARS-CoV-2.What is the most favorite and original chemistry developed in your research group?My favorite chemistries are always those that enable efficient access to drug molecules.How do you get into this specific field?Could you please share some experiences with our readers?The virus uses nucleosides as raw materials for replication.Learned from this biological process,I have been devoted to,for decades,synthesizing nucleoside mimics.Once attached to the 3'-hydroxy group of the virus RNA chain,these nucleoside analogs can effectively inhibit virus replication.Hard work pays off!We have developed a series of novel 4’-modified nucleosides,among which Azvudine has been officially approved for treating HIV in China and COVID-19 in both China and Russia.Notably,Azvudine is the first Chinese oral anti-COVID-19 agent.The experiences I would like to share with the readers are many,but emphases are placed on thinking critically and working enthusiastically.How do you supervise your students?I generally supervise students differently according to their aptitudes.For those keen on scientific work,I always suggest them learn from the literature,and practice makes perfect,think critically,and work with passion.What is the most important personality for scientific research?The personalities such as curiosity,creativity,persistence,and the ability to think critically and solve problems matter most for scientific research.Furthermore,what sets successful scientists apart is their passion for their work and their ability to persevere in facing challenges and setbacks.Who influences you mostly in your life?My Ph.D.supervisor profoundly fuels my passion for academia and,to some extent,reshapes my personality.