Interfering with Nucleic Acid Synthesis: Recent Progress of Nucleoside and Nucleotide Analogues in Anti-viral Treatment
Selina Huang 1
1The Baylor School
ABSTRACT
Nucleoside/nucleotide analogues are a group of drugs that interfere with the synthesis of DNA or RNA, and have been used for anti-viral treatment for decades. Their importance is self-evident due to their ubiquitous mechanism of action, especially as we today face the challenge of COVID-19 pandemic. Here we review recent studies regarding nucleoside/nucleotide analogues in HIV, HBV, HCV, herpes and influenza virus infection, as well as the emerging SARS-CoV-2 infection, so as to shed light its current status of usage, and also to project the anti-viral strategy in the future.
Index Terms—Antiviral drugs, nucleoside/nucleotide analogue, viral infection
Introduction
prevalence of viral infections across the world have been gravely threatening the public health.
With hepatitis infection as a notable example, 325 million people globally by 2020 are suffering from it1. Novel diseases like coronavirus disease 2019 (COVID-19), having infected nearly 90 million people since its advent to January 20212, is still causing disastrous outbreaks, which shows the inability of human to response adeptly to such novel challenge.
One type of antiviral drug, being nucleoside/nucleotide analogues, is a synthetic, chemically modified compound that mimics the structure of natural nucleosides or nucleotides, both of which are the building blocks of DNA and RNA.3 Pharmacologically, nucleoside/nucleotide analogues can disrupt or terminate the synthesis of viral DNA or RNA (Figure 1) 4. Given that these processes are universal among viruses, many nucleoside/nucleotide analogues have relatively broad-spectrum efficacy5.
Based on their drug targets, nucleoside/nucleotide analogues can be classified as reverse transcriptase inhibitors, DNA polymerase inhibitors, and RNA polymerase inhibitors. A typical reverse transcriptase inhibitor is zidovudine, which is mostly used against HIV6. It is a synthetic thymidine nucleoside analogue that has its 3’ hydroxy group replaced by an azido group7, and this modification allows it to inhibit viral reverse transcription and to induce cDNA chain termination8. One example of DNA polymerase inhibitors is acyclovir, which is commonly used against viral infections caused by viruses of herpesvirus family9. Acyclovir is a synthetic purine nucleoside analogue that inhibits viral DNA polymerase by interrupting the growing viral DNA chain and terminating further polymerization10. An RNA polymerase inhibitor, remdesivir, is a monophosphoramidateprodrug of 1'-cyano-substituted adenosine nucleoside analogue that terminates viral RNA synthesis by inhibiting viral RNA polymerase11. More drugs of each category are listed in Table 1.
In this review we will discuss how nucleoside/nucleotide drugs have evolved, and especially highlight their recent research in antiviral treatment. Five different viral infection is used as examples, including HIV, hepatitis, herpes, influenza, and SARS-CoV-2.
Nucleoside/Nucleotide Analogues in HIV Treatment
Human immunodeficiency virus (HIV) is a retrovirus that infects the host T lymphocytes through CD4 receptors and a co-receptor that can be CC-chemokine receptor 5 (CCR5) or CXC- chemokine receptor 4 (CXCR4)13. By depleting CD4+ T cells, HIV is the cause of acquired
immune deficiency syndrome (AIDS)14. The main feature of HIV that makes HIV infection difficult to be completely cured is that it is able to have its DNA integrated into the host genome, making an HIV reservoir13,15. On the other hand, since HIV undergoes reverse transcription for its replication, this process can be inhibited by reverse transcriptase inhibitors13. Examples of reverse transcriptase inhibitors for HIV treatment are emtricitabine, lamivudine, stavudine, and zidovudine5. Ganciclovir, a DNA polymerase inhibitor and is originally used for herpes simplex virus (HSV) treatment, is also a nucleoside analogue that can treat HIV infections5,16.
Emtricitabine, an analogue of cytidine, was first discovered in 1996 when its metabolites were identified from human urine sample in a clinical trial of anti-HIV compound17. Emtricitabine can serve as HIV post-exposure prophylaxis (PEP) when combined with tenofovirdisoproxilfumarate and rilpivirine18. Contradicting to previous belief, a recent study showed that the combination of emtricitabine, tenofovir and ritonavir-boosted lopinavir as antiretroviral therapy (ART) to treat pregnant women with HIV do not lead to a higher risk of premature birth and death of infants than zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV–3TC–LPV/r) did19. Moreover, it is worth noting that when virally suppressed HIV-positive patients switch from non-integrase inhibitor-based antiviral therapy to a co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir
alafenamide (E/C/F/TAF), they may experience moderate weight gain and significant increase in lipid levels20.
Lamivudine is a cytidine nucleoside analogue that was the unnatural enantiomer derived from 2’-Deoxy-3’-thiacytidine (BCH 189), a potent anti-HIV agent21. Upon its advent, lamivudine continues to be able to partner with existing and novel therapies, and combination therapies with lamivudine had become more potent, safer, and more convenient in past years22. Lamivudine combined with
Table 1.List of major nucleoside and nucleotide analogue drugs.
Drug Name Types of Analogue Virus Target Reference
Reverse Transcriptase Inhibitors
Emitricitabine cytidine HIV, HBV [17-20]
Lamivudine cytidine HIV, HBV [5], [21-26], [52]
Stavudine thymidine HIV [27-30]
Zidovudine thymidine HIV [31-34]
Entecavir guanine HBV [42-44]
Tenofovir adenine HIV, HBV [5], [39], [45-47]
Adefovir adenine HBV [39], [48-52]
Telbivudine thymidine HBV [53-56]
DNA Polymerase inhibitors
Ganciclovir guanine HIV, CMV [35-37], [80,81]
Valganciclovir guanine CMV [35-37]
Clevudine thymidine HBV [57-58]
Acyclovir guanine HSV [68-70]
Valaciclovir guanine HSV [68-70]
Penciclovir guanine HSV [70-73]
Famciclovir guanine HSV [70-73]
Brivudine thymidine VZV [5], [74-76]
Cidofovir cytidine CMV [77-79]
RNA Polymerase inhibitors
Favipiravir pyrazine Influenza B virus [93-98], [111]
Ribavirin guanine HCV, Influenza virus, SARS-CoV-
2 [11], [103-108]
Sofosbuvir uridine HCV, SARS-CoV-2 [39], [59-60], [85-
89], [109]
2’FdG guanine Influenza A virus [39], [61-62], [110]
Galidesivir adenine Ebola, SARS-CoV-2 [90-92]
Figure 1.Mechanism of action of nucleoside/nucleotide analogues.
Both nucleoside analogue and nucleotide analogue are phosphorylated upon cell entry to become active. The final triphosphate metabolites interact with viral enzymes and terminate the synthesis DNA or RNA.12
dolutegravir can be a promising maintenance therapy for virally controlled HIV-positive patients23 and a potential treatment for patients with HIV infection24,25. However, lamivudine monotherapy (LM) has led to immune decline when used on HIV-positive children who were previously receiving combination antiretroviral therapy (cART)26.
Stavudine, an analogue of thymidine, was developed to treat HIV infection and was approved for medical use in 199627. Overall, the use of stavudine for HIV-positive patients is declining due to its side affects28,29.For example, using it is likely causing a higher risk of getting neuropathy28. Nevertheless, synthesized phosphoramidate derivatives of stavudine with different polyfluorinated variants to the aromatic ring (4-CF3 / 3-CF3 / 3-SF5) have shown potentials in exhibiting better anti-HIV activity and lower toxicity than unmodified stavudine30.
Zidovudine is a thymidine analogue that was first found as potential agent against HIV infection in 198531 but had been limited in performance of viral resistance, efficacy, and safety and needed further studies32. The combination of zidovudine and lamivudine has the potential to treat HIV-associated neurocognitive disorder given its ability to localize the brain reigns in which HIV neurodegeneration occurs33. The use of zidovudine for pregnant women with HIV has a strong association with cardiac remodeling, which can lead to clinical heart failure and cardiovascular disease, and cardiac dysfunction of fetuses34.
Ganciclovir is an analogue of guanine that inhibits DNA polymerase, initially developed to treat herpesvirus infection with or without HIV infection35,36. A recent study has shown that ganciclovir is able to directly reduce HIV viral load by inhibiting HIV reverse transcription37. Nucleoside/nucleotide Analogues in Hepatitis Treatment
Hepatitis is the inflammation occurred in the liver that can be caused by bacteria, parasite, alcohol, auto-immune, etc., and it is mostly caused by virues38. The viruses causing hepatitis can be classified into hepatitis A, B, C, D, E, G viruses, in which hepatitis A, B, and C viruses are the most common38. Both hepatitis A virus (HAV) and hepatitis C virus (HCV) are single strand RNA viruses that undergo RNA replication directly38,39, while hepatitis B virus (HBV) is a circular double strand DNA virus that undergoes DNA repair, transcription, and reverse transcription for its replication40. Chronic hepatitis B and C infection can lead to death of hepatocytes, acute liver injury, fibrosis and cirrhosis, liver cancer, etc.38. According to WHO estimate, there are 71 million people that have chronic hepatitis C virus infection by 202041. Currently, there are no drugs for HAV treatment, and major available nucleoside/nucleotide analogues for treating HBV and HCV infection are lamivudine, entecavir, tenofovir, clevudine, adefovir, emtricitabine, telbivudine, ribavirin, and sofosbuvir5.
Entecavir, a guanosine analogue that inhibits reverse transcription of HBV, was firstly introduced in 2002 with superior antiviral activity against HBV than lamivudine42. A recent research has shown that the combination of entecavir and traditional Chinese medicine (TCM) could lead to significant improvements in patients’ hyaluronidase (HA), laminin protein (LN), type III procollagen (PCIII), type IV collagen (IV-C), alanine transaminase (ALT) and aspartate transaminase (AST) negative conversion rates43. In another study, the combination of entecavir with TCM Tiao-Gan-Yi-Pi granule (TGYP) and Tiao-Gan-Jian-Pi-Jie-Du granule (TGJPJD) has demonstrated better Hepatitis B e antigen (HBeAg) clearance comparing with entecavir monotherapy44.
Tenofovir is an adenosine monophosphate analogue that inhibits reverse transcription5,39, and it was seen as a promising agent for treating HIV infection back in 2002 because it belongs to the class acyclic nucleoside phosphonates, which demonstrated activity against a broad range of viruses including HBV45. Compared with entecavir, the usage of tenofovir was associated with a lower risk of hepatocellular carcinoma (HCC) in treating chronic hepatitis B infection46 and better efficacy in 3 months treatment duration47. However, in long-term treatment, the performances of tenofovir and of entecavir have no significant differences, and tenofovir is associated with higher risk to suffer from renal damage and hypophosphatemia47.
Adefovir is an analogue of deoxyadenosine monophosphate which inhibits reverse transcription of HBV, and adefovirdipivoxil is its prodrug39. It appeared as a new option to treat HBV in 2003 with it being effective and well tolerated48, and later study had shown that its efficacy could last after 3 years of therapy with low rates of viral resistance49. In a recent research, the comparison of adefovir and tenofovir led to the conclusion that adefovir is more likely to have better serological responses while tenofovir could decrease renal function and bone mineral density50. Though in another study, comparing the combination therapy of entecavir/adefovir to tenofovirmonotherapy, the combination of entecavir and adefovir had the higher potential to cause hypophosphatemia and renal impairment51.
Lamivudine, already introduced in the previous section, was the first nucleoside drug approved by U.S. Food and Drug Administration (FDA) to treat HBV infection5. In a study comparing its efficacy when combined with tenofovir versus when combined with adefovir, lamivudine combining with adefovir was proved to be an effective alternative of combination therapy of
lamivudine and tenofovir in long-term HBV treatment for patients infected by both HIV and HBV52.
Telbivudine is a thymidine analogue that inhibits reverse transcription of HBV53. It is effective and safe to treat pregnant women and patients with risk of renal impairments because it can protect renal function54,55. It can also reduce maternal transmission of HBV for women with chronic hepatitis B and 12 weeks of gestation56. However, telbivudine could lead to lactic acidosis and, when combined with pegylated interferon alpha-2a, neuropathy55.
Clevudine, firstly approved in Korea, is a thymine analogue that inhibits HBV DNA polymerase with little toxicity57. Though a recent research said that the usage of clevudine for about 14 months may lead to reversible mitochondria myopathy58.
Ribavirin is a broad-spectrum guanosine analogue that is primarily used to treat HCV infection39. It was known as virazole in 1972 and was recognized with its ability to inhibit viral RNA and DNA synthesis effectively59. Recently, a study suggested that ribavirin could influence lipid and apolipoprotein parameters and reduce the change of lipid metabolism caused by HCV60. Sofosbuvir, usually used with other drugs, is a uridine analogue that inhibits HCV RNA polymerase39. 12 weeks of its usage with velpatasvir, an NS5a inhibitor of HCV, has resulted in superior rates of sustained virologic response than that of sofosbuvir and ribavirin combination therapy for patients with or without previous treatment61.Also, the combination therapy of sofosbuvir/velpatasvir for 12 weeks can be an effective and well tolerated therapy for HCV patients with decompensated cirrhosis, while adding ribavirin to the combination merely leads to higher toxicity causing adverse events and abnormalities62.
Nucleoside/Nucleotide Analogues in Herpes Treatment
Herpesviruses are the viruses that cause herpes infection5. Eight species of them are discovered currently, and, among them, the most common ones include herpes simplex viruses (HSV-1 and HSV-2), varicella zoster virus (VZV), and cytomegalovirus (CMV)5,63. HSV-1 and HSV-2 usually cause oral, labial or genital infection with symptom of watery blister63,64. VZV infection causes varicella (chickenpox) in children and zoster (shingles) for adults if reactivated65. CMV infection is mostly asymptotic, but it is opportunistic and can threaten immunocompromised patients66. According to WHO estimates, 67% and 13% of people worldwide have been infected by HSV-1 and HSV-2 respectively67. One important feature of herpesviruses is their latent infection, leaving their DNA as episome in the nuclei of infected cells64,66. In treating infection caused by herpesviruses, commonly used nucleoside analogues include acyclovir, valaciclovir, penciclovir, famciclovir, brivudine, cidofovir, ganciclovir, and valganciclovir5.
Acyclovir is a guanine analogue that inhibits viral DNA polymerase and, as mentioned in the introduction, is primarily used to treat HSV infection68. The prodrug of acyclovir, valaciclovir, compared to acyclovir, has a higher oral bioavailability and is more convenient to use69. A recent research showed that the usage of acyclovir on immunocompromised patients was likely to cause changes in HSV-2 thymidine kinase that led to acyclovir resistance70.
Penciclovir is also a guanine analogue that inhibits DNA polymerase mainly used to treat HSV infection71. Its prodrug is famciclovir, which has a higher oral availability72. Penciclovir is rather safe to use, with evidence from an experiment using it to treat HSV infected cats73. The experiment showed that penciclovir was well-tolerated and had no systemic toxicity or adverse effects73. Because of penciclovir’s and famciclovir’s similar structures with acyclovir’s, they are also likely to lead to drug resistant HSV by similar mechanism as mentioned previously70.
Brivudine, a thymidine analogue, is a potent DNA polymerase inhibitor firstly approved in Europe to treat VZV5,74. Comparing with famciclovir and valaciclovir in treating VZV, brivudine has been shown the ability to control pain of patients faster75. However, a recent study
showed that, since brivudine has a pyrimidine ring similar to that of fluorouracil, a drug associated with corony spasm, it can potentially lead to Kounis syndrome76.
Cidofovir, a cytidine analogue, is mostly used to treat CMV infection77. Recently, it was reported to have led to mutations in CMV genes, making the disease nonresponsive and drug- resistant78. It could also be used with acyclovir and amenamevir to treat HSV-1 infection79.
Ganciclovir, as mentioned before, is primarily used to treat CMV35,36. Its prodrug is valganciclovir80. In treating symptomatic congenital CMV disease, the usage of valganciclovir for 6 months, comparing with 6 weeks, has led to slightly better hearing, which might be helpful against sensorineural hearing losscaused by CMV81.
Nucleoside/Nucleotide Analogues in Influenza Treatment
Looking at the past, influenza had caused disastrous outbreaks. During the 2009 influenza A H1N1 pandemic, there was a global death toll of more than 280,000 according to the estimation82. Influenza is an acute respiratory disease caused by influenza viruses83. Influenza viruses are classified into A, B, and C according to the antigens found on their envelopes, and those antigens are hemagglutinin (HA), neuraminidase (NA) and M proteins (M1 and M2)83,84. Within the envelope, influenza viruses have a negative-sense single strand RNA and undergo transcription by the activity of their protein complex RNA dependent RNA polymerase (RdRp), which includes polymerase basic 1 (PB1), PB2, and polymerase acidic (PA) for influenza A and influenza B viruses and polymerase 3 (P3) for influenza C viruses83,84. Major drugs used for treating influenza infection are neuraminidase inhibitors such as zanamivir and oseltamivir, and there are also drugs such as pimodivir and baloxavir targeting PA and PB2 of RdRp83. Nucleoside analogues, targeting PB1 in this case, are not popularly used to treat influenza, but there are still relevant studies about using ribavirin, 2’-deoxy-2’-fluoroguanosine (2’FdG), and favipiravir to treat influenza83,.
Ribavirin, as mentioned before, is mainly used to treat HCV39. It was first found effective in treating influenza A and influenza B infections in mice when combined with amantadine85, but later studies suggested that although ribavirin was highly effective against influenza A and influenza B in vitro, the data of using it in vivo were inconsistent, thus preventing it from being approved86,87. The efficacy of ribavirin combined with other drugs is still being studied. In a recent research, the combination of ribavirin/oseltamivir/amantadine had decreased more viral shedding than oseltamivirmonotherapy did, but this difference did not improved clinical results88. Another recent research administering ribavirin in juvenile mice found that ribavirin could reduce inflammation and respiratory immune response in treating influenza infection89.
2’FdG, a purine 2’-deoxy-2’-fluorociboside synthesized from 2’-deoxy-2’-fluoridine, has a 2-aminos substituent on its purine ring90. It first demonstrated potent antiviral activity against influenza A virus in 199390, and it works by blocking transcription of influenza virus RNA90. In 2000, 2’FdG was shown to be not suitable for clinical use because it could be incorporated into human DNA by human DNA polymerase, showing a lack of specificity that would increase the drug’s toxicity91. A reagent similar to 2’FdG, 2’-deoxy-2’-fluorocytidine (2’-FdC), known for its potential of being an effective antiviral, can have the same problem91,92.
Favipiravir is a pyrazine analogue that was approved in Japan for emergency use in 201493. It can effectively prevent lethal infection both on mice with wild type influenza B virus and on mice with oseltamivir-resistant influenza B virus94. Comparing with oseltamivirmonotherapy, the combination of oseltamivir/favipiravir can lead to clinical recovery faster 95. This combination may also expediate viral extinction because of the strong association between oseltamivir resistance mutation and favipiravir induced mutations that were harmful to viral growth96. However, it could also allow higher frequencies of NA mutations that may lead to
drug resistance96. Combined with another drug, zanamivir, favipiravir has been demonstrated effective in a case of severe influenza B infection in a severely immunocompromised child, and further studies suggested that in vitro the combination can decrease viral load significantly and clear zanamivir-resistant influenza B viruses97. One recent research reveals a possible way for a favipiramir-resistant influenza virus to evolve, in which two mutations are crucial: K229R in PB1 subunit that prevents incorporation of favipiravir into viral RNA with the cost of hurting viral fitness and P653L in PA subunit that compensates for the drawback of the previous mutation98. Nucleoside/Nucleotide Analogues in COVID-19 Treatment
COVID 19, a novel disease first appeared in 2019, has already caused 1,930,265 deaths by January 20212. Its pathogenic agent is severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), which is a positive-sense single-stranded RNA virus99. It enters human body through the binding between its S protein and angiotensin converting enzyme 2 (ACE2) on the cell surface, infecting the upper respiratory tract first and then the lower respiratory tract, and the infection could occur in multiple organs and lead to systematic inflammation100. In severe cases, pulmonary infection is induced, accompanied by immune dysfunction99. Therefore, three most common symptoms of COVID-19 are fever, cough, and shortness of breath, and SARS-CoV-2 spread via respiratory droplets as infected people cough, sneeze, etc.101 Due to the urgency of facing the challenge COVID-19 brought, many efforts were made to develop drugs targeting every aspect of SARS-CoV-2’s life cycle including cell entry, protease function, etc.102 Several nucleoside/nucleotide analogues, targeting the RNA replication of SARS-CoV-2, are also being tested102. There are remdesivir, ribavirin, sofosbuvir, favipiravir, and galidesivir102.
Remdesivir, already mentioned previously, is an adenosine nucleotide analogue, and its active metabolite is GS-44152411,103. First introduced in 2016, remdesivir was known as a broad spectrum antiviral drug mainly used for treating Ebola infection103. In October 2020, it was approved by FDA to treat COVID-19104. Animal studies were performed to test the efficacy of remdesivir in vivo105,106. In one study, it was tested on rhesus macaque, and the results showed that remdesivir has led to clinical benefits such as reduction in pulmonary infiltrates and virus titres105. Additionally, the study noted that the efficacy of remdesivir could decrease with delay of treatment105. In clinical trials, more information about remdesivir is obtained106,107. A clinical trial performed in February 2020 at Hubei, China, showed that although not statistically significant, patients receiving remdesivir reached clinical improvement faster than those receiving placebo108. This trial did not bring a significant result due to inadequate patients, but a lager clinical trial later supported its finding107,108. It was a globalized trial with 1063 patients, and it showed that remdesivir can not only lead to clinical improvements in a shorter time than placebo can, but also prevent progression to more severe respiratory diseases107.
Ribavirin is introduced in previous parts. It combined with interferon beta- 1b/ritonavir/lopinavir was shown to be able to reduce time of viral shedding and hospital stay of patients with COVID-19 in its phase II trial in Hong Kong109.
Sofosbuvir, also already introduced, has been tested in a small-scale trial in Iran in its efficacy to treat COVID-19110. It was combined with daclatasivir, and the results showed that it can reduce the time of hospital stay and mortality and lead to clinical improvements faster110. Moreover, it had less side effects than Ribavirin110.
Favipiravir was mentioned in the part focusing on influenza. A small-sized clinical trial of using it to treat COVID-19 was conducted in Japan, and, although it was found to have no significant effects in improving viral clearance, it has led to defervescencefaster111.
Galidesivir is an adenosine analogue that was first found effective against filovirus disease such as Ebola112. In an experiment using molecular docking, galidesivir was able to bind
SARS-CoV-2 RdRp, indicating its potential to hinder the polymerase function and to be used against coronavirus infection113.
Conclusion
Nucleoside/nucleotide analogues are not new to us. They have been existing for decades and are still effective antiviral weapons. Chemical modifications improved their efficacy, specificity and the route of administration114. Their generally applicable mechanism of action makes them tend to be broad-spectrum87, 98,112
, making the potential of co-usage with other drugs and drug re- purposing49,114, which provides a faster approach in advent of novel virus infection such as SARS-CoV-2. However, the disadvantage of nucleoside/nucleotide analogues also lies in their mechanism of action, which is the reason for many side effects such as hepatic injury39. Moreover, drug-drug interaction can also affect the safety of nucleoside/nucleotide analogues when they are co-administered with other drugs115.
In the future, the use of nucleoside/nucleotide analogues will continue to play an important role in treating virus infection. Computational techniques, such as molecular docking, as well as the advance in structural biology can help to predict drug action, facilitating the process of drug repurposing113,116. In fact, molecular docking was already used to predict drug action for potentially effective drugs against SARS-Cov-2113. In the long term, further observations in the use of nucleoside/nucleotide analogues can lead to a more comprehensive understanding regarding their safety.
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