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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0000000000000007
TREATMENT OPTIMISATION: Edited by David H. Brown Ripin, Charles W. Flexner and Ben Plumley

Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

Hurwitz, Selwyn J.a,b; Schinazi, Raymond F.a,b

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aLaboratory of Biochemical Pharmacology, Department of Pediatrics, Center for AIDS Research, Emory University School of Medicine, Atlanta, Georgia, USA

bVeterans Affairs Medical Center, Decatur, Georgia, USA

Correspondence to Professor Raymond F. Schinazi, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Center for AIDS Research, Emory University School of Medicine, 1760 Haygood Drive, Room 418, Atlanta, GA 30322, USA. Tel: +1 404 727 1414; fax: +1 404 417 1330; e-mail: rschina@emory.edu.

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Abstract

Purpose of review: This review focuses on the chemical and pharmacological rationale behind the development of nucleoside antiviral prodrugs (NAPs).

Recent findings: Highly efficacious NAPs have been developed that extend and improve the quality of lives of individuals infected with HIV and hepatitis B virus (HBV), herpes viruses, and adenovirus infection in immunocompromised individuals. A very high rate of hepatitis C virus (HCV) cure is now possible using NAPs combined with other direct acting antiviral agents (DAAs).

Summary: Prodrug strategies can address the issues of poor oral bioavailability and delivery of active metabolites to the targeted cells. Additionally, NAPs demonstrate potential for improving deficiencies in oral absorption, metabolism, tissue distribution, cellular accumulation, phosphorylation, and overall potency, in addition to diminishing potential for in-vivo selection of resistant viruses. NAPs continue to be the backbone for the treatment of HIV and HBV, herpesviruses, and adenovirus infections because their active forms are potent, have long intracellular half-lives and are relatively safe with high barrier to resistance.

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INTRODUCTION

Nucleoside antiviral inhibitors (NAIs) have been developed to treat herpes simplex virus (HSV), HIV-1, hepatitis B virus (HBV), and hepatitis C virus (HCV) [1–6]. NAIs are phosphorylated by various cellular kinases to their respective NAI-triphosphate (NAI-TP) forms. NAI-TP compete with the natural nucleotide triphosphates (NTPs) for incorporation by the viral polymerases (V-pol) of HIV-1 (reverse transcriptase), HBV (DNA pol), and HCV (RNA dependent pol, RdRp, NS5B). NAI-TP serve as obligatory chain terminators when they lack a 3′-hydroxyl group on the sugar moiety and as nonobligatory chain terminators when the sugar 3′-hydroxy group is ineffective at chain elongation. In-vivo viral dynamic profiles of NAI depend on their pharmacokinetics, cellular accumulation, and potencies of NAI-TP versus V-pol, and the point of antiviral activity in the viral replication cycle. For example, NAI-TP act primarily on HIV-1 reverse transcriptase prior to integration of HIV-1 into host cell DNA. Once reverse transcription is complete and viral DNA has integrated into host cell DNA, the NAI-TP has no further effect on HIV-1 replication in that cell. The net effect is to block new infections of CD4+ cells, so that the maximal decline rate in plasma HIV-1 reflects the death rate of infected CD4+ lymphocytes [7,8]. In contrast, HBV and HCV do not have preintegration reverse transcriptase steps, and NAI-TP directly inhibit the viral replication in infected cells. Consequently, HBV and HCV plasma decay rates directly reflect the degree of inhibition of the targeted V-pol by the NAI-TP and the subsequent clearance of virus from plasma [9,10▪]. The therapeutic index of NAIs depends on the cellular accumulation of the NTP, the intracellular half-life, and the relative affinities of the NAI-TP for the V-pol versus host nuclear and/or mitochondrial DNA or RNA-pol[11▪]. The initial phosphorylation step for NAI may be rate limiting and bypassed by administering a modified NAI containing a masked monophosphate such as a phosphoramidate moiety. An esterase-driven intracellular unmasking to the monophosphate and subsequent phosphorylation by intracellular kinases provides the active NAI-TP form [12]. For phosphonates, phosphonylalkyl esters are widely utilized to mask the polar nature of the NAI to improve the overall pharmacokinetics of phosphonate delivery and subsequent intercellular kinase-driven active NAI-diphosphate formation. This approach was used with the acyclic phosphonate NAI, tenofovir disoproxil fumarate (TDF), as tenofovir-diphosphate has potent activity versus HIV-1 reverse transcriptase and HBV-pol[13]. Tenofovir (TFV) has been used as a ‘backbone’ structure for a variety of prodrugs including TDF (as the disoproxil fumarate), alafenamide fumarate (TAF), and hexadecyloxy-TFV (CMX157) described in this review. Structures and trade names of major compounds in this review are summarized in Figs. 1–4.

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Modulating oral absorption and tissue distribution of nucleoside antiviral inhibitors using prodrugs
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Most NAIs are hydrophylic (polar) and passively diffuse poorly through lipid bilayers, including the gastrointestinal tract. Many NAIs are actively transported by one or more of the proteins from the solute-membrane-carrier superfamily of the intestine and target cells [14]. However, acyclic NAIs (e.g., acyclovir, penciclovir, and TFV) are poor substrates for the various gastrointestinal transporters and have limited oral bioavailability, hence the need for prodrug approaches for improving their bioavailability. Various approaches have been explored for improving the intestinal absorption of NAI, including the addition of amino-esters, and less commonly phospholipid moieties onto phosphonate NAI. Other experimental approaches for targeted delivery of NAI include nanoparticle formulations [15].

Nucleoside antiviral prodrugs (NAPs) are typically absorbed through the intestine by diffusion due to their overall lipophilicity, which may be influenced by their charge, molecular weight, and stability under gastric pH, as well as resistance to esterases in the intestine and liver [16]. Their subsequent systemic distribution depends on resistance to first-pass metabolism in the liver and enzymes in the serum, as well as their cellular permeability. For example, valinyl and acetyl ester prodrugs improved the oral absorption of acyclovir (prodrug valacyclovir hydrochloride) and penciclovir (prodrug famciclovir) by 15–70% [17–20], making these agents useful for oral treatment of herpes zoster infections (Fig. 1) [21]. The metabolism of famciclovir to penciclovir in the liver is catalyzed by aldehyde oxidase and other enzymes [22–25]. The negatively charged acyclic NAI TFV is poorly absorbed orally (<2% in mice, 17% in dogs, and 5.3% in monkeys) [26–28]. However, the addition of two alkyl methyl carbonate ester moieties improved oral absorption to approximately 20% in humans, sufficient to make TDF a clinically viable drug for oral administration (Fig. 2). None of these prodrugs appear to be sufficiently stable in the intestine or during first-pass liver metabolism to deliver quantifiable concentrations of the parent NAI prodrug into the circulation. Similarly, amdoxovir, the orally absorbed amine prodrug of beta-D-dioxolane guanosine (DXG) is rapidly absorbed and deaminated to the active NAI by ubiquitous adenosine deaminase, producing a ratio of areas under the plasma concentration versus time curves (AUC ratio), amdoxovir:DXG of 20 : 80% (Fig. 2) [29].

Although HIV-1 acute infections primarily involve CD4+ lymphocytes, other tissues (e.g., lymphatic tissues and central nervous system) may also contribute to disease morbidity, and could serve as viral sanctuaries and reservoirs of infection [11▪]. Therefore, it was desirable to develop NAI prodrugs with efficient delivery to the systemic circulation in their intact forms. The TFV prodrugs, TAF and CMX157, have good oral absorption and enhanced penetration into lymphatic tissues (Fig. 2). Increased lipophilicity increases volumes of distribution (e.g., into body fat), but may further enhance cellular accumulation. CMX001 is a lipophilic prodrug of cidofovir (used to treat cytomegalovirus, CMV) with the same lysolecithin-type moiety as CMX157 (Fig. 4). This moiety was engineered from lysophosphatidylcholine, by replacing the acyl ester bond at the sn-1 position with an ether linkage, which prevents hydrolysis of the acyl group by lysophospholipase during absorption. Also, the hydroxyl at the sn-2 position of glycerol in lysophosphatidylcholine was replaced with a hydrogen atom, which prevents reacylation by lysophosphatidylcholine acyltransferases present in small intestinal enterocytes and other tissues. The phosphonate (-P-CH2-) linkage to the acyclic nucleoside on these NAPs is stable to cleavage by a phospholipase D or a phosphodiesterase. The resulting prodrug moiety remained primarily susceptible to metabolic cleavage by the phospholipase C enzyme, which is absent in plasma and pancreatic secretions, but is present intracellularly. Therefore, these NAPs remain stable during oral absorption and are transported intact in plasma to peripheral tissues [30]. The intact lipophilic moiety facilitates penetration into lymphatic tissues and into the brain via the blood–brain barrier [31,32]. TAF, CMX157, and CMX001 are cleaved intracellularly, releasing the NAI phosphonates, which are subsequently phosphorylated by cellular kinases to the active phosphoramidate-diphosphate. High cellular levels and stability of the phosphoramidate-diphosphate improved antiviral potency allowing for less frequent dosing than parent NAI [31]. In-vitro studies of CMX157 and CMX001 demonstrated greater than 90% reduction in cellular accumulation (in hOAT1-expressing cells and control cells) in the presence of 20% serum, indicating that the passive uptake of both compounds is reduced by binding to serum protein [31,33]. TAF and the HCV drug, sofosbuvir (Fig. 3) undergo rapid stereospecific hydrolysis of the carboxyl ester by human cathepsin A (CatA) at lysosomal pH, and more slowly by carboxyl esterase 1 (CES1). Hepatocytes contain high levels of CatA; consequently, the majority (about ∼70%) of TAF is metabolized in liver tissue to TFV (TAF is also being developed to treat HBV). However, the remaining approximately 30% of TAF that reaches systemic circulation is sufficient to produce higher concentrations of TFV in CD4+ lymphocytes at 30 mg per day than from TDF administered at a 300 mg dose making it suitable for the treatment of HIV-1. Increased cellular accumulation of TFV corresponds to elevated cellular concentrations of TFV-diphosphate, and generally greater antiviral efficacy. TFV is transported by the organic anion transporters (OATs) in the renal tubule and demonstrates renal toxicity. However, TAF and CMX157 are not actively transported by OAT, which may be advantageous.

Because HBV and HCV primarily infect hepatocytes, there are advantages in developing prodrugs, which deliver NAIs more specifically to the liver. Sofosbuvir (PSI-7977, GS-7977) is a single diastereoisomer phosphoramidate prodrug of PSI-7851, which undergoes rapid stereospecific intracellular hydrolysis of the amino acid carboxyl ester by CatA to ultimately form PSI-6206-MP (2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-MP; Fig. 3). Interestingly, the parent unphosphorylated uridine analogue is not active against HCV. As CatA is expressed at high concentrations in hepatocytes, oral administration of sofosbuvir produced very high hepatocyte concentrations of PSI-6206-MP, whereas plasma concentrations of sofosbuvir or any of its metabolites remain low, which could limit systemic toxicity [34]. PSI-6206-MP is then phosphorylated by cellular kinases to the PSI-6206-TP, which inhibits HCV NS5B [34]. In addition, the active metabolite of sofusbuvir (PSI-6206-TP) has a long intracellular t1/2 (48 h) compared with its corresponding C analogue (PSI-6130-TP, 4.7 h) [35▪▪,36].

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Use of relevant models for predicting first-in-human doses

The diversity of prodrug moieties incorporated in NAPs markedly influences their physical-chemical properties, and hence their tissue distribution and metabolism. Prior to phase 1 testing, the plasma clearance (clearance = dose/AUC) of a new NAP in humans is unknown, and the diverse pharmacokinetic profiles of NAP makes scaling of first-in-human (FIH) doses much less predictable than for non-prodrug NAI. FIH doses of NAPs are usually scaled using data from experiments performed in vitro and in animals, using similar methods used for other classes of drugs. A commonly used method for predicting clearance in humans involves the use of allometric equations, which assume that species metabolic rates (and hence drug clearance) are proportional to body weight raised to an exponent (usually ∼0.74) [37]. Provided plasma concentrations remain proportional to dose (linear), the predicted clearance in humans can be used to calculate average plasma concentrations at steady state (Css average) for a given dose (D) administered at a set dose interval (τ), using the formula: Css_average = D/(clearance × τ). Allometric scaling is often unreliable, but predictions may be further refined by incorporating differences in drug binding to plasma proteins in the allometric equations [38]. Because drug clearance may be influenced by differences in enzyme levels and enzyme activity between species, other approaches make use of in-vitro measurements of drug stability in liver microsomal extracts [39]. Another level of uncertainty in predicting FIH doses of NAPs may arise from the susceptibility of various prodrugs to metabolism by intestinal carboxyesterases, which can vary between species [16]. Detailed physiological pharmacokinetics modeling approaches using organ blood flow rates together with enzyme data require more extensive data, and are computationally intensive [40–42]. The importance of using an appropriate species for dose scaling was illustrated by a phase 1 trial of GS-6620 (an early C-nucleoside HCV polymerase inhibitor), which was terminated by Gilead Sciences (Foster City, California, USA) due to unacceptable variations in drug absorption and viral responses, despite highly reproducible plasma concentrations in dogs [43▪].

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HIGHLIGHTED NUCLEOSIDE ANTIVIRAL PRODRUGS

TAF (GS-7340; Gilead Sciences) is an orally absorbed isopropylalaninyl monoamidate phenyl monoester prodrug of TFV in phase 3 development for the treatment of HIV (Fig. 2). TAF is approximately 400-fold more potent than TFV at inhibiting HIV replication in human peripheral blood mononuclear (PBM) cells [44], and is approximately 200-fold more stable than TDF to extracellular esterases. TAF is converted by CatA and various other serine and cysteine proteases to an alanine metabolite of TFV (TFV-Ala), which rapidly degrades to TFV under the acidic pH of lysozymes [45]. Single dose pharmacokinetics studies in dogs demonstrated that TAF was more than 70% absorbed after oral administration (Tmax ∼1 h), was more rapidly cleared from plasma than TFV, and produced a 34-fold greater 24-h exposure (AUC0–24) of TFV in PBM cells than in plasma. Following administration of 10 mg-eq/kg of 14C-labeled TAF or TDF, peripheral tissue contents of 14C-labeled metabolites were generally higher after administration of TAF than after TDF. Higher amounts of 14C-labeled metabolites were detected in the bile after TAF administration. Furthermore, levels of metabolites were five-fold to 15-fold higher in lymphatic tissues compared with TDF [44]. Therefore, TAF has potential for improved targeting of lymphatic tissue versus TDF. TAF administration resulted in a 40% increase in 14C-labeled metabolites in the liver compared with TDF, indicating its promise for the treatment of HBV. A single dose drug metabolism and pharmacokinetic study in eight healthy male volunteers that administered 25 mg oral 14C-TAF revealed that TAF was extensively metabolized and eliminated in the feces and urine, mainly as TFV. The predominant metabolite detected in plasma was uric acid, consistent with purine metabolism [46]. An in-vitro viral breakthrough experiment in 293T cells that accumulated sufficient TFV-diphosphate to mimic levels observed in the clinic during treatment with TDF and TAF, demonstrated a high degree of potency against most mutant NRTI-resistant HIV isolates. However, this was not the case at TFV-diphosphate concentrations equivalent to those achieved in vivo using TDF. Virus breakthrough was not inhibited for strains harboring more than five thymidine analogue mutations (TAMs), at TFV-diphosphate concentrations achievable in vivo for either prodrug. This study concluded that TAF may be beneficial for individuals harboring certain resistant viruses [47]. The K65R mutation is a ‘hallmark’ resistance mutation of TFV and is associated with virologic failure in individuals administered TDF [48]. The utility of TFV prodrugs may be extnded if they are coadministered with an NAI with ‘resistance repellant’ properties versus K65R such as zidovudine (ZDV). However, ZDV has dose-limiting bone marrow toxicities [49]. Therefore, TFV prodrugs could be coadministered with an NAI having K65R potency similar to ZDV, for example, EFdA (4′-ethynyl-2-fluoro-2′-deoxyadenosine), provided those drugs are less toxic than ZDV [50▪].

TAF has superior antiviral efficacy at lower doses than TDF [51,52]. For example, a 10-day monotherapy study in HIV-1-infected individuals administered 8, 25, or 40 mg TAF once daily for 10 days, compared with a standard 300 mg dose of TDF produced five-fold to seven-fold higher TFV-diphosphate levels in primary human lymphocytes, and approximately 0.5-fold greater average decreases in log10 serum viral loads with the 25 and 40 mg doses. The TFV systemic exposure at these TAF doses was reduced by 90% compared with TDF [51]. A phase 2 trial comparing TAF or TDF coadministered in a single tablet with elvitegravir, cobicistat, and emtricitabine, demonstrated comparable efficacy with both regimens. However, a statistically significant decrease in bone density (P = 0.005), and smaller increases in serum creatinine were observed for the TAF regimen [53▪].

CMX157 (Chimerix, Durham, North Carolina, USA, – licensed to Merck Pharmaceuticals, Whitehouse Station, New Jersey, USA), also known as hexadecyloxypropyl tenofovir is undergoing phase 2 clinical development for treatment of HIV infection (Fig. 2; http://www.marketwatch.com/story/merck-inks-two-pacts-for-investigational-hiv-drug-2012–07–24, accessed 17 July 2013). CMX157 was 267-fold more active than TFV against HIV-1 when evaluated in PBM cells [54]. In addition to HIV-reverse transcriptase inhibition by TFV-diphosphate chain termination, the improved potency may involve binding of CMX157 to cell-free virions through direct insertion into viral envelope, and subsequent facilitated delivery of TFV into infected cells [55].

A phase 1 randomized blinded, dose-escalation trial in healthy volunteers comparing the pharmacokinetics of a standard TDF dosage with escalating doses of CMX157 (between 25 and 400 mg), demonstrated both safety and tolerability. Active TFV-diphosphate remained detectable for 6 days in the PBM cells of individuals administered a single 400 mg of CMX157, suggesting the possibility of a convenient, once per week dose regimen [31] (http://ir.chimerix.com/releasedetail.cfm?ReleaseID=752310 accessed 23 July 2013).

CMX001 (Chimerix) has potent activity versus herpes and other double-stranded viruses, and is in development for the treatment of smallpox under the Animal Efficacy Rule (21 CFR 314; Fig. 4) [56,57]. CMX001 is being evaluated in phase II clinical trials for the prophylaxis and pre-emption of CMV infection in stem cell transplant patients (study CMX001–201; http://clinicaltrials.gov/ct2/show/NCT00942305); pre-emptive treatment of adenovirus (ADV) disease following stem cell transplantation in adults and children (study CMX001–202; http://clinicaltrials.gov/ct2/show/study/NCT01241344); and an open label study that allows for treatment of patients with a wide range of serious and/or life-threatening dsDNA virus diseases (CMX001–350; http://clinicaltrials.gov/show/NCT01143181, Accessed 22 July 2013). A phase 1 study in healthy volunteers demonstrated rapid absorption (Tmax ∼3 h), good tolerability, and a dose proportional AUC. A dose-dependent terminal plasma t1/2 of 6–24 h was observed at single doses between 0.25 and 2 mg/kg, and multiple doses (three total doses; administered every 6 days) between 0.1 and 1 mg/kg [32]. A retrospective study was performed with 13 immune-compromised, ADV-infected patients, treated with intravenous cidofovir for 5–90 days (median = 21 days), followed by oral CMX001 administered under fasting conditions, via gastric tube at doses ranging from 1 to 3 mg/kg per week for up to 6 months, or until a viral response defined as a more than 99% decrease in adenoviral DNA copies/ml in serum from baseline [58▪]. Eight patients had more than 1 log10 drop in serum ADV DNA copies/ml in week 1 of therapy, and nine demonstrated a viral response by week 9 (median 7 days, range: 3–35 days). Changes in absolute lymphocyte counts at week 6 were inversely related to change in log10 viral load (r = −0.74; P = 0.03). Persons with a viral response survived longer (median 196 versus 54.5 days; P = 5.04). No serious adverse events were attributed to CMX001. In a phase 2 study of CMX001 as pre-emptive therapy for ADV infection, in allogeneic hematopoietic cell transplant recipients, a 100 mg twice per week dose demonstrated decreased levels of ADV viremia and showed a potential benefit in reducing both progression to ADV disease and all-cause mortality, compared with participants who received placebo or CMX001 given once per week. Planned intent-to-treat analyses and exploratory analyses in specific patient groups consistently favored this regimen over placebo, although statistical significance was not established in this exploratory study (http://finance.yahoo.com/news/chimerix-announces-top-line-data-100000101.html).

Sofosbuvir (Gilead Sciences) and mericitabine (Roche Laboratories, Nutley, New Jersey, USA) are prodrugs of NAI with origins connecting back to PSI-6130 (β-D-2′-deoxy-2′-α-fluoro-2′-β-C-methyl-cytidine; Fig. 3). PSI-6130 is a NAI discovered by Pharmasset Inc. (now Gilead Sciences), which demonstrates potent anti-HCV activity using a replicon assay [59]. Mericitabine is an ester prodrug of PSI-6130 prodrug, licensed to Roche Laboratories, which is undergoing phase 2b testing [60]. Mechanistic studies indicated that PSI-6130 is phosphorylated to the monophosphate, diphosphate, and triphosphate forms when incubated with hepatocytes [35▪▪,36,61]. Also, PSI-6130-TP was found to be a potent inhibitor of HCV NS5B via chain termination [61]. However, the uridine derivative of PSI-6130, PSI-6206 was inactive against HCV, as it was not phosphorylated to PSI-6206-MP (PSI-7411) by cellular nucleoside kinases [35▪▪,36]. Cell-based metabolism studies with primary human hepatocytes indicated that PSI-6130 is a unique compound that gives rise to two nucleoside triphosphates that are both potent inhibitors of the HCV NS5B. Subsequent enzymatic studies demonstrated that PSI-7411, once formed from PSI-6130-MP by 2′-deoxycytidylate deaminase, was phosphorylated to its diphosphate, PSI-7410, by UMP-CMP kinase and the TP form, PSI-7409, by nucleoside diphosphate kinase [35▪▪]. Furthermore, enzymatic inhibition studies using the replicon assay and purified recombinant HCV NS5B demonstrated that PSI-7409 was indeed a potent inhibitor of HCV RNA replication [35▪▪,36]. Consequently, a phosphoramidate derivative, PSI-6206 was synthesized to bypass the initial phosphorylation step, which yielded PSI-7581, comprising a mixture of two active diastereoisomers, PSI-7976 (Rp) and PSI-7977 (Sp). Sofosbuvir, the more potent and more stable Sp isomer, is undergoing phase 3 clinical testing for the treatment of HCV in combination with other antiviral agents [62–65]. The cellular metabolism of sofosbuvir is complex, and has been studied in detail [34]. Briefly, the carboxyl ester of PSI-7581 is hydrolyzed stereo-selectively by human CatA and CES1 in hepatocytes. PSI-7977 is a better substrate for CatA and CES1, which ultimately provides a higher concentration of the 5′-MP (PSI-7411), which is consistent with its more potent activity versus HCV replication. This enzymatic deesterification is followed by a putative nucleophilic attack on the phosphorus by the carboxyl group releasing a molecule of phenol, and the alaninyl phosphate metabolite, PSI-352707, common to both diastereomers. Removal of the amino acid moiety of PSI-352707 is then catalyzed by histidine triad nucleotide-binding protein 1 (Hint1), yielding the 5′-MP nucleoside PSI-7411, which is phosphorylated to the diphosphate, PSI-7410, and to the active NAI-TP (PSI-7409), by UMP-CMP kinase and nucleoside diphosphate kinase, respectively.

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CONCLUSION

Despite demonstrating potency and limited toxicity in vitro, many NAIs are not suitable for clinical development due to pharmacokinetic (absorption, tissue accumulation, metabolism, and elimination) deficiencies. NAP is a well-established approach for altering the physicochemical and hence the pharmacokinetics and phosphorylation of these NAIs. The choice of an appropriate NAP moiety also has an effect on efficacy and safety, by enhancing distribution into virus susceptible tissues (e.g., hepatocytes for HBV/HCV, or lymphatic tissue for HIV), while shielding tissues associated with side-effects (e.g., TAF, but not TDF shields renal tubules from TFV). In addition, some NAIs can be dosed less frequently such as hexadecyloxypropyl tenofovir, which could improve adherence for HIV (or HBV)-infected persons. The chemistry used in the development of NAP continues to become more sophisticated, and has progressed from the use of simple acetates to amino acid esters to phosphoramidates and lipophilic hexadecyloxy. The application of NAP technology has been wide and impactful, and has made it possible to achieve high cure rates for HCV infections, for example, sofosbuvir when combined with other direct acting antiviral agents. Likewise, CMX001 may be a promising therapeutic option for the treatment of severe ADV disease in immunocompromised patients. Although, to date, there is no effective cure for HIV and HBV infections, progression to symptomatic disease can be halted or delayed in most infected persons by using a combination of agents targeting the various V-pol involved in viral replication. The field of nucleoside chemistry and biology continues to produce numerous highly effective NAIs, with improved oral bioavailability and drug delivery to infected tissues, for the treatment of HIV, HBV, and HCV. These drugs have prolonged the lives of millions of infected persons. The ultimate goal in antiviral research is to find affordable cures for chronic infections that produce significant reductions in global morbidity and mortality.

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Acknowledgements

None.

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Conflicts of interest

This work was supported in part by NIH grants 5P30-AI-50409 (CFAR), and 1RO1MH100999, and by the Department of Veterans Affairs

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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Keywords:

adenovirus; antiviral agents; hepatitis B virus; hepatitis C virus; HIV; herpes simplex virus; nucleoside antiviral agents; prodrugs

© 2013 Lippincott Williams & Wilkins, Inc.

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