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Viruses Sep 2022My collaboration with Prof. Antonín Holý, that spans a period of 3-4 decades (1976-2012), led to the discovery of several acyclic nucleoside phosphonates (ANPs) which...
My collaboration with Prof. Antonín Holý, that spans a period of 3-4 decades (1976-2012), led to the discovery of several acyclic nucleoside phosphonates (ANPs) which were clinically developed by Gilead Sciences: cidofovir, adefovir, and tenofovir. The latter was further converted to two orally bioavailable prodrug forms, TDF and TAF, and both TDF and TAF were further combined with other antiviral drugs, thus giving rise to a broad array of antiviral drug combinations for the treatment of HIV infections. TDF and TAF are both available for the treatment of hepatitis B virus (HBV) infections, and, in combination with emtricitabine, also applicable as Truvada and Descovy, respectively, for the prophylaxis of HIV infections.
Topics: Anniversaries and Special Events; Anti-HIV Agents; Antiviral Agents; Cidofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; HIV Infections; Hepatitis B; Hepatitis B virus; Humans; Nucleosides; Organophosphonates; Prodrugs; Tenofovir
PubMed: 36146783
DOI: 10.3390/v14091978 -
Frontiers in Chemistry 2022Compounds with a phosphonate group, i.e., -P(O)(OH) group attached directly to the molecule a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various... (Review)
Review
Compounds with a phosphonate group, i.e., -P(O)(OH) group attached directly to the molecule a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called "open-ring" derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44-80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).
PubMed: 35668826
DOI: 10.3389/fchem.2022.889737 -
Antiviral Research Aug 2023Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox (formerly monkeypox). Identifying novel and potent antiviral...
Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox (formerly monkeypox). Identifying novel and potent antiviral compounds is critical to successful drug development targeting poxviruses. Here we tested two compounds, nucleoside trifluridine, and nucleotide adefovir dipivoxil, for antiviral activities against vaccinia virus (VACV), mpox virus (MPXV), and cowpox virus (CPXV) in physiologically relevant primary human fibroblasts. Both compounds potently inhibited the replication of VACV, CPXV, and MPXV (MA001 2022 isolate) in plaque assays. In our recently developed assay based on a recombinant VACV expressing secreted Gaussia luciferase, they both exhibited high potency in inhibiting VACV replication with ECs in the low nanomolar range. In addition, both trifluridine and adefovir dipivoxil inhibited VACV DNA replication and downstream viral gene expression. Our results characterized trifluridine and adefovir dipivoxil as strong poxvirus antiviral compounds and further validate the VACV Gaussia luciferase assay as a highly efficient and reliable reporter tool for identifying poxvirus inhibitors. Given that both compounds are FDA-approved drugs, and trifluridine is already used to treat ocular vaccinia, further development of trifluridine and adefovir dipivoxil holds great promise in treating poxvirus infections, including mpox.
Topics: Animals; Humans; Vaccinia virus; Vaccinia; Cowpox virus; Antiviral Agents; Trifluridine; Mpox (monkeypox); Cell Line; Poxviridae
PubMed: 37270160
DOI: 10.1016/j.antiviral.2023.105651 -
Clinics in Liver Disease Nov 2023In treatment-naïve patients with chronic hepatitis B virus (HBV) infection, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide have a... (Review)
Review
In treatment-naïve patients with chronic hepatitis B virus (HBV) infection, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide have a minimal or no risk of drug-resistance. These 3 nucleos(t)ide analog agents are highly potent inducing high rate of virologic response (reducing serum HBV DNA to levels undetectable by polymerase chain reaction assays) in most treatment-naïve patients. Our randomized trials have demonstrated that monotherapy with TDF can provide a successful virological response in most of the heavily pretreated patients with multidrug resistance to ETV or adefovir.
Topics: Humans; Hepatitis B, Chronic; Antiviral Agents; Treatment Outcome; Tenofovir; Drug Therapy, Combination; Hepatitis B virus
PubMed: 37778771
DOI: 10.1016/j.cld.2023.05.005 -
Viruses May 2023Base pairing based on hydrogen bonding has, since its inception, been crucial in the antiviral activity of arabinosyladenine, 2'-deoxyuridines (i.e., IDU, TFT, BVDU),...
Base pairing based on hydrogen bonding has, since its inception, been crucial in the antiviral activity of arabinosyladenine, 2'-deoxyuridines (i.e., IDU, TFT, BVDU), acyclic nucleoside analogues (i.e., acyclovir) and nucleoside reverse transcriptase inhibitors (NRTIs). Base pairing based on hydrogen bonding also plays a key role in the mechanism of action of various acyclic nucleoside phosphonates (ANPs) such as adefovir, tenofovir, cidofovir and O-DAPYs, thus explaining their activity against a wide array of DNA viruses (human hepatitis B virus (HBV), human immunodeficiency (HIV) and human herpes viruses (i.e., human cytomegalovirus)). Hydrogen bonding (base pairing) also seems to be involved in the inhibitory activity of Cf1743 (and its prodrug FV-100) against varicella-zoster virus (VZV) and in the activity of sofosbuvir against hepatitis C virus and that of remdesivir against SARS-CoV-2 (COVID-19). Hydrogen bonding (base pairing) may also explain the broad-spectrum antiviral effects of ribavirin and favipiravir. This may lead to lethal mutagenesis (error catastrophe), as has been demonstrated with molnutegravir in its activity against SARS-CoV-2.
Topics: Humans; Antiviral Agents; Nucleosides; Base Pairing; Hydrogen Bonding; COVID-19; SARS-CoV-2; Viruses
PubMed: 37243232
DOI: 10.3390/v15051145 -
Frontiers in Cellular and Infection... 2023Liver inflammation is the main risk factor for developing liver fibrosis, cirrhosis, and even hepatocellular carcinoma in chronic hepatitis B (CHB) patients. To replace...
BACKGROUNDS & AIMS
Liver inflammation is the main risk factor for developing liver fibrosis, cirrhosis, and even hepatocellular carcinoma in chronic hepatitis B (CHB) patients. To replace biopsy, additional non-invasive biomarkers to diagnose and grade liver necroinflammation are urgently required in clinical practice.
METHOD
Ninety-four CHB patients, including 74 HBeAg-positive and 20 HBeAg-negative patients, were enrolled and started entecavir or adefovir therapy. Serum HBV RNA, HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), ALT and AST levels, as well as intrahepatic HBV DNA and cccDNA were measured at baseline and during treatment. Liver inflammation was assessed at baseline and month 60 by liver biopsy. Inflammation regression was defined as a ≥1-grade decrease according to the Scheuer scoring system.
RESULTS
In HBeAg-positive CHB patients, at baseline, serum HBsAg and HBcrAg levels negatively correlated with inflammation grade, while ALT and AST levels positively correlated with inflammation grade. AST plus HBsAg exhibited excellent diagnostic ability for significant inflammation with an AUROC of 0.896. After 60 months of antiviral treatment, almost all the patients' liver inflammation ameliorated to G1, and no patients had inflammation progression.
CONCLUSION
Besides ALT and AST, serum HBsAg and HBcrAg correlated with inflammation grade in HBeAg-positive CHB patients before NAs treatment. Moreover, the combination of HBsAg and AST exhibited excellent diagnostic ability for significant inflammation.
Topics: Humans; Hepatitis B Surface Antigens; Hepatitis B, Chronic; Hepatitis B e Antigens; Hepatitis B virus; DNA, Viral; DNA, Circular; Hepatitis B Core Antigens; Antiviral Agents; Inflammation; Liver Cirrhosis; Liver Neoplasms; Biomarkers
PubMed: 37065191
DOI: 10.3389/fcimb.2023.1083912 -
Frontiers in Immunology 2022Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of...
BACKGROUND
Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical.
METHODS
This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis.
RESULTS
The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A.
CONCLUSIONS
For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.
Topics: Allografts; Antiviral Agents; Creatinine; Fanconi Anemia; Fanconi Syndrome; Humans; Kidney Transplantation; Kidney Tubules, Proximal; Renal Insufficiency; Retrospective Studies; Scoliosis; Tacrolimus
PubMed: 36059468
DOI: 10.3389/fimmu.2022.979983 -
JHEP Reports : Innovation in Hepatology Apr 2023Pegylated interferon alpha (pegIFNα) is commonly used for the treatment of people infected with HDV. However, its mode of action in HDV-infected cells remains elusive...
BACKGROUND & AIMS
Pegylated interferon alpha (pegIFNα) is commonly used for the treatment of people infected with HDV. However, its mode of action in HDV-infected cells remains elusive and only a minority of people respond to pegIFNα therapy. Herein, we aimed to assess the responsiveness of three different cloned HDV strains to pegIFNα We used a previously cloned HDV genotype 1 strain (dubbed HDV-1a) that appeared insensitive to interferon-α , a new HDV strain (HDV-1p) we isolated from an individual achieving later sustained response to IFNα therapy, and one phylogenetically distant genotype 3 strain (HDV-3).
METHODS
PegIFNα was administered to human liver chimeric mice infected with HBV and the different HDV strains or to HBV/HDV infected human hepatocytes isolated from chimeric mice. Virological parameters and host responses were analysed by qPCR, sequencing, immunoblotting, RNA hybridisation and immunofluorescence staining.
RESULTS
PegIFNα treatment efficiently reduced HDV RNA viraemia (∼2-log) and intrahepatic HDV markers both in mice infected with HBV/HDV-1p and HBV/HDV-3. In contrast, HDV parameters remained unaffected by pegIFNα treatment both in mice (up to 9 weeks) and in isolated cells infected with HBV/HDV-1a. Notably, HBV viraemia was efficiently lowered (∼2-log) and human interferon-stimulated genes similarly induced in all three HBV/HDV-infected mouse groups receiving pegIFNα. Genome sequencing revealed highly conserved ribozyme and L-hepatitis D antigen post-translational modification sites among all three isolates.
CONCLUSIONS
Our comparative study indicates the ability of pegIFNα to lower HDV loads in stably infected human hepatocytes and the existence of complex virus-specific determinants of IFNα responsiveness.
IMPACT AND IMPLICATIONS
Understanding factors counteracting HDV infections is paramount to develop curative therapies. We compared the responsiveness of three different cloned HDV strains to pegylated interferon alpha in chronically infected mice. The different responsiveness of these HDV isolates to treatment highlights a previously underestimated heterogeneity among HDV strains.
PubMed: 36908749
DOI: 10.1016/j.jhepr.2023.100673 -
Infection and Drug Resistance 2022To investigate the efficacy and safety of antiviral drugs in the treatment of coronavirus disease 2019 (COVID-19). (Review)
Review
OBJECTIVE
To investigate the efficacy and safety of antiviral drugs in the treatment of coronavirus disease 2019 (COVID-19).
METHODS
All clinical trials of antiviral drug treatment for COVID-19 from December 2019 to December 2021 in CNKI, PubMed, Embase, Wanfang and VIP databases were searched by computer, and the results were systematically reviewed.
RESULTS
A total of 21 studies were included, including 5 randomized controlled studies, 5 non-randomized controlled studies, 3 retrospective cohort studies, 6 retrospective case series studies, and 2 observational studies, with a total of 2118 patients. The evaluated drugs included Ridzevir, Lopinavir/Ritonavir, Jingluwa, Fapiravi, Abidor, Danorivir, and interferon α. The evaluated antiviral drugs did not show superior efficacy for COVID-19 in clinical trials. In terms of safety, particular attention needs to be paid to the gastrointestinal side effects of lopinavir/ritonavir and the serious side effects of redsivir.
CONCLUSION
There is no specific drug. Antiviral drugs have a greater therapeutic benefit for mild and usual patients, and in severe patients, lopinavir/ritonavir may not be effective. For critically ill patients, adefovir or more than two antiviral drugs can be used early. Antiviral drugs combined with traditional Chinese medicine treatment is effective. In view of the safety of the drug, it is necessary to consider the increase of serum uric acid caused by fapravi, the increase of bilirubin caused by abidol, and the gastrointestinal reactions of pitavir. In addition, other adverse reactions should also be noted.
PubMed: 35983302
DOI: 10.2147/IDR.S362946 -
Biochemical Pharmacology Mar 2021Since the 1950s, great efforts have been made to develop antiviral agents against many infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus... (Review)
Review
Since the 1950s, great efforts have been made to develop antiviral agents against many infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV). Among the list of nearly 106 antiviral agents approved in the past five decades, Prof. Erik De Clercq has contributed to the development of 7 antiviral drugs: tenofovir disoproxil fumarate (Viread®) for HIV and HBV treatment, tenofovir alafenamide (Vemlidy®) for HIV and HBV treatment, brivudine (Zostex®) for HSV-1 and VZV treatment, valacyclovir (Valtrex®) for HSV and VZV treatment, adefovir dipivoxil (Hepsera®) for HBV treatment, stavudine (Zerit®) for HIV treatment, and cidofovir (Vistide®) for treating HCMV retinitis in AIDS patients. In addition to the above antiviral drugs, his contributions include two anti-cancer drugs: rabacfosadine (Tanovea®-CA1) for canine lymphoma and plerixafor (Mozobil®) for multiple myeloma and non-Hodgkin's lymphoma. These achievements are driven by his life-long passions for antiviral research and successful collaborations worldwide. To honor the 80th birthday of Prof. Erik De Clercq, this study highlights his scientific achievements and the importance of life-long passions and collaborations in the success of antiviral research and drug development.
Topics: Anniversaries and Special Events; Antiviral Agents; Biomedical Research; Drug Development; Faculty; HIV Infections; Hepatitis C; Humans; Male
PubMed: 33617841
DOI: 10.1016/j.bcp.2021.114485