Penciclovir Research Articles

Novel electrochemical sensor based on MoS2NSs@AgNPs/MWCNTs-COOH nanocomposites for effective detection of Penciclovir

Abnormal levels of penciclovir (PCV) in humans may lead to inflammation and renal impairment, and its frequent detection in the aquatic environment poses environmental hazards. Consequently, timely detection and regulation of PCV concentrations in the human body are crucial for drug research, disease diagnosis, and environmental protection. In this study, a PCV electrochemical sensing platform based on MoS2NSs@AgNPs/MWCNTs-COOH was constructed by in situ reduction of silver nanoparticles (AgNPs) on MoS2 nanosheets (MoS2NSs) and complexed with carboxylated multi-walled carbon nanotubes (MWCNTs-COOH). The synergistic effect of highly conductive AgNPs, high surface area MoS2NSs, and MWCNTs-COOH increased the electron transfer rate at the electrode surface and thus effectively promoted the electrooxidation process of PCV. The electrochemical performance of the sensor was investigated and optimized by cyclic voltammetry (CV) and linear scanning voltammetry (LSV). The linear response of PCV under optimal conditions was in the range of 0.5–200.0 µM, with a limit of detection (LOD) of 0.039 µM (S/N = 3), and recoveries of 98.1–101.1 %, 95.6–101.6 %, 97.0–103.6 %, and 96.0–100.9 %. The results show that the constructed MoS2NSs@AgNPs/MWCNTs-COOH /GEC sensing platform has the advantages of high sensitivity, fast response speed, and strong anti-interference ability. This work is the first to develop an electrochemical sensing platform for PCV based on MoS2NSs@AgNPs/MWCNTs-COOH, providing a new PCV quantitative detection solution.

Combined Effect of Basic Antiherpetic Drugs with a New Inhibitor of the Terminase Complex of Herpes Simplex Virus Type 1 in Vero Cell Cultures.

Carriers of herpes simplex virus type 1 (HSV-1) account for more than 90% of the global population. Infection manifests itself in the formation of blisters and ulcers on the face or genitals and can cause blindness, encephalitis, and generalized infection. All first- and second-line modern antiherpetic drugs selectively inhibit viral DNA polymerase. The purine-benzoxazine conjugate LAS-131 ((S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine), which we have described earlier, uses the large subunit of the HSV-1 terminase complex as a biotarget and selectively inhibits HSV-1 reproduction in vitro. Basically new results were for the first time obtained to characterize the combined effect on human herpesvirus infection for LAS-131 used in combination with practically significant antiviral compounds, including the nucleoside analogs acyclovir (ACV), penciclovir (PCV), ganciclovir (GCV), brivudine (BVdU), iododeoxyuridine (IdU), and adenine arabinoside (Ara-A); the nucleoside phosphonate analog cidofovir (CDV); and the pyrophosphate analog foscarnet (FOS). A cytopathic effect (CPE) inhibition assay showed that the drug concentration that inhibited the virus-induced CPE by 50% decreased by a factor of 2 (an additive effect, FOS) or more (a synergistic effect; ACV, PCV, GCV, IdU, BVdU, Ara-A, and CDV) when the drugs were used in combination with LAS-131. Nonpermissive conditions for HSV-1 reproduction were thus created at lower drug concentrations, opening up new real possibilities to control human herpesvirus infection.

Molecular interaction of antiviral drug penciclovir with DNA and HSA insights from experimental and docking studies

One approach to accelerate the availability of new cancer drugs is to test drugs approved for other conditions as anticancer agents. During recent decades, penciclovir (PNV) has been frequently utilized as a potent antiviral drug, in particular against infections caused by herpes viruses. Many antivirals interact with DNA and change their expression level, so determining the binding mode is of great importance. In our laboratory, we have focused our attention to design improved drugs that target cellular DNA, to understand the mechanism of action at the molecular level, and also to investigate the effect of antiviral drugs as anticancer agents. The results of ct-DNA-PNV interactions at physiological pH using fluorescence spectroscopy, UV–visible absorption spectroscopy, and molecular modeling reveal this drug binds well to ct-DNA through groove binding. The circular dichroism measurements displayed that PNV caused a slight change in the DNA structure which affirmed that the binding of PNV with the DNA occurs through the groove mode. Besides, multi-spectroscopic and molecular docking were used to evaluate how PNV interacts with human serum albumin under physiological conditions. The findings of fluorescence quenching suggested that static quenching was involved in the spontaneous development of HSA-PNV complex through hydrophobic force. The docking simulation results validated the findings of spectroscopic techniques. Communicated by Ramaswamy H. Sarma

Novel deliberately sensitive and selective penciclovir voltammetric sensors depending on iron oxide nanoparticles carbon paste electrodes

The present study described the construction and electroanalytical characterization of a novel penciclovir (PCV) voltammetric carbon paste sensor fortified with iron oxide nanoparticles (FeONPs/CPEs). Integration of the electrode matrix with iron oxide nanoparticles obviously enhanced the PCV oxidation peak based on its electrocatalytic activity towards the electrooxidation of PCV molecule at the electrode surface. At the optimized pH value, PCV exhibited an irreversible oxidation peak at about 1.03 V following a diffusion–reaction mechanism. Differential pulse voltammograms (DPVs) registered peak current values correlated linearly to the corresponding PCV within the concentration range from 0.09 to 4.656 µg mL−1 PCV with LOD value 0.025 µg mL−1. Based on the electrochemical behavior of PCV at various pH and the scan rate values, and with the aid of molecular orbital calculations, the electrooxidation reaction of PCV molecule undergoes through oxidation of the terminal amino group of the guanine moiety with the participation of one electron and two protons. Based on the reported selectivity and sensitivity of the FeONPs/CPE, PCV can be assayed in pharmaceutical formulations, biological fluids and surface water samples with average recoveries agreeable with the official HPLC-UV method.

Optimization of Thymidine Kinase-Based Safety Switch for Neural Cell Therapy.

Cell therapies based on pluripotent stem cells (PSC), have opened new therapeutic strategies for neurodegenerative diseases. However, insufficiently differentiated PSC can lead to tumor formation. Ideally, safety switch therapies should selectively kill proliferative transplant cells while preserving post-mitotic neurons. In this study, we evaluated the potential of nucleoside analogs and thymidine kinase-based suicide genes. Among tested thymidine kinase variants, the humanized SR39 (SR39h) variant rendered cells most sensitive to suicide induction. Unexpectedly, post-mitotic neurons with ubiquitous SR39h expression were killed by ganciclovir, but were spared when SR39h was expressed under the control of the cell cycle-dependent Ki67 promoter. The efficacy of six different nucleoside analogs to induce cell death was then evaluated. Penciclovir (PCV) showed the most interesting properties with an efficiency comparable to ganciclovir (GCV), but low toxicity. We tested three nucleoside analogs in vivo: at concentrations of 40 mg/kg/day, PCV and GCV prevented tumor formation, while acyclovir (ACV) did not. In summary, SR39h under the control of a cell cycle-dependent promoter appears most efficient and selective as safety switch for neural transplants. In this setting, PCV and GCV are efficient inducers of cell death. Because of its low toxicity, PCV might become a preferred alternative to GCV.

Oral gel loaded with penciclovir–lavender oil nanoemulsion to enhance bioavailability and alleviate pain associated with herpes labialis

Herpes labialis, caused by herpes simplex virus type 1, is usually characterized by painful skin or mucosal lesions. Penciclovir (PV) tablets are found to be effective against herpes labialis but suffer from poor oral bioavailability. This study aimed to combine the benefits of PV and lavender oil (LO), which exhibits anesthetic activity, in the form of a self-nanoemulsifying drug delivery system (SNEDDS) for the treatment of herpes labialis. Toward this purpose, LO (oil), Labrasol:Labrafil M1944 CS in the ratio of 6:4 (surfactant mixture), and Lauroglycol-FCC (co-surfactant, selected based on the solubility of PV) were evaluated as the independent factors using a distance quadratic mixture design. The formulation was optimized for the minimum globule size and maximum stability index and was determined to contain 14% LO, 40.5% Labrasol:Labrafil 1944 (6:4), and 45.5% Lauroglycol-FCC. The optimized PV-LO-SNEDDS was embedded in chitosan hydrogel and the resulting formulations coded by (O3) were prepared and evaluated. The rheological studies demonstrated a combined pseudoplastic and thixotropic behavior with the highest flux of PV permeation across sheep buccal mucosa. Compared to a marketed 1% PV cream, the O3 formulation exhibited a significantly higher and sustained PV release, nearly twice the PV permeability, and a relative bioavailability of 180%. Overall, results confirm that the O3 formulation can provide an efficient delivery system for PV to reach oral mucosa and subsequent prolonged PV release. Thus, the PV-LO-SNEDDS embedded oral gel is promising and can be further evaluated in clinical settings to establish its therapeutic use in herpes labialis.

Rapid, sensitive detection of ganciclovir, penciclovir and valacyclovir-hydrochloride by artificial neural network and partial least squares combined with surface enhanced Raman spectroscopy

Surface enhanced Raman spectroscopy (SERS) plays important role in qualitative analysis, identification and bio-imaging analysis, but the difficulty of quantitative analysis still exists. Here, we established quantitative prediction models for ganciclovir (GCV), penciclovir (PCV) and valacyclovir-hydrochloride (VACV-HCl) by adopting chemometric methods including artificial neural network (ANN) and partial least squares (PLS) algorithms combined with SERS based on concentrated Ag nanoparticles. The limit of detection for three drugs reached 1.0 × 10−6 mol L−1 and the detection time was less than 4 min for a single sample, which demonstrated that SERS detection is rapid and sensitive. Comparing with the PLS models, the ANN models established in this paper showed better performance, the root mean square error of prediction and correlation coefficients of prediction for GCV, PCV and VACV-HCl were 0.0009245, 0.0002237, 0.0003307 and 0.8991, 0.9867, 0.9880, respectively. These results indicated that the established ANN models are robust and accurate. Subsequently, the ANN models combined with SERS were applied to detect VACV-HCl tablets and rat plasma spiking GCV and PCV. Overall, chemometrics combined with SERS in this paper provides a new reference for analytes to develop a rapid and sensitive quantitative analysis method.

Development of nanoemulsions containing penciclovir for herpes simplex treatment and a liquid chromatographic method to drug assessment in porcine skin layers

A successful formulation (penciclovir hydrogel nanoemulsion - HN) to be used in transdermal drug delivery route to treat herpes simplex virus was developed and an analytical method to quantify penciclovir (PCV) in porcine ear skin was stablished and validated. PCV nanoemulsions were prepared by high pressure homogenization and presented spherical mean droplet size 180 nm. The association efficiency and zeta potential were 87% and– 27 mV, respectively. The bioanalytical method developed showed specificity for the interferences from the skin matrixes (epidermis and dermis) and the linearity was in the range 0.1 – 25 μg/mL of drug, The mean recovery data for the three levels tested were 95.2% for the epidermis and 97.3% for the dermis and adequate results were obtained for repeatability and inter-day precision. In vitro percutaneous absorption studies with the PCV nanoemulsion and a market cream were conducted employing the porcine skin.The cumulative amounts of PCV permeated from cream and HN, 8 h after dosing, were 2.60 and 4.15 μg/cm², respectively, representing a quite higher flux and a much higher permeability coefficient for the developed formulation. It can be concluded that HN provide a good skin targeting effect and may be a promising carrier for topical delivery of penciclovir.

In vitro Transporter Screens to Investigate Uremic Solute‐Drugs Interaction

Renal tubule secretion via transporter proteins plays a critical role in the renal clearance of drugs and endogenous compounds. We hypothesize that competition between accumulating uremic solutes and drugs for proximal tubule transport results in unpredictable drug exposure in people with kidney disease. The goal of this study was to characterize the potential of prominent uremic solutes, including hippuric acid (HA), indoxyl sulfate (IS), p‐cresol sulfate (pCS) and trimethylamine N‐oxide (TMAO), to inhibit renal tubule transport. We used penciclovir (PEN), oseltamivir carboxylate (OST) and tenofovir (TEN) in our study as model transporter substrates. We conducted systemic screens of transporter inhibition using in vitro assays, including uptake (overexpressed cell lines) and efflux (in‐side out vesicle membranes) transporters, to investigate whether uremic solutes and model drugs are potential inhibitors/substrates of renal uptake and efflux transporters involved in tubular secretion (OAT1/2/3, MRP2/4, MATE1/2K, P‐gp, BCRP). This systematic study of uremic solute ‐ drug interaction demonstrated that some uremic solutes and drugs (PEN and TEN) might compete and inhibit uptake transporters via OATs and efflux via MRPs transporters. A clearer understanding of the interactions between drugs and uremic solutes may lead to personalized approaches for the selection and dosing of medications in people with kidney disease.Support or Funding Information5 R01 GM 121354‐02 UREMIA TRANSPORTThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Synthesis and anti-HSV activity of tricyclic penciclovir and hydroxybutylguanine derivatives.

A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C6H4) displayed good inhibitory activity (HSV-1 EC50 1.5 μM, HSV-2 EC50 0.8 μM) and retained inhibitory activity in HSV-1 TK- cells (EC50 0.8 μM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds.

Relevance of non-synonymous thymidine kinase mutations for antiviral resistance of recombinant herpes simplex virus type 2 strains

Therapy or prophylaxis of herpes simplex virus type 2 (HSV-2) infections with the nucleoside analog aciclovir (ACV) can lead to the emergence of drug-resistant HSV-2 strains, particularly in immunocompromised patients. In this context, multiple amino acid (aa) changes can accumulate in the ACV-converting viral thymidine kinase (TK) which hampers sequence-based diagnostics significantly. In this study, the so far unknown or still doubted relevance of several individual aa changes for drug resistance in HSV-2 was clarified. For this purpose, ten recombinant fluorescent HSV-2 strains differing in the respective aa within their TK were constructed using the bacterial artificial chromosome (BAC) pHSV2(MS)Lox. Similar TK expression levels and similar replication behavior patterns were demonstrated for the mutants as compared to the unmodified BAC-derived HSV-2 strain. Subsequently, the resulting strains were tested for their susceptibility to ACV as well as penciclovir (PCV) in parallel to a modified cytopathic effect (CPE) inhibition assay and by determining the relative fluorescence intensity (quantified using units, RFU) as a measure for the viral replication capacity. While aa changes Y53N and R221H conferred ACV resistance with cross-resistance to PCV, the aa changes G25A, G39E, T131M, Y133F, G150D, A157T, R248W, and L342W maintained a susceptible phenotype against both antivirals. The CPE inhibition assay and the measurement of relative fluorescence intensity yielded comparable results for the phenotypic testing of recombinant viruses. The latter test showed some technical advantages. In conclusion, the significance of single aa changes in HSV-2 TK on ACV/PCV resistance was clarified by the construction and phenotypic testing of recombinant viral strains. This was facilitated by the fluorescence based method.

Biophysical and In Silico Studies of the Interaction between the Anti-Viral Agents Acyclovir and Penciclovir, and Human Serum Albumin.

Acyclovir (ACV) and penciclovir (PNV) have been commonly used during the last few decades as potent antiviral agents, especially for the treatment of herpes virus infections. In the present research their binding properties with human serum albumin (HSA) were studied using different advanced spectroscopic and in-silico methods. The interactions between ACV/PNV and HSA at the three investigated temperatures revealed a static type of binding. Extraction of the thermodynamic parameters of the ACV-HSA and PNV-HSA systems from the measured spectrofluorimetric data demonstrated spontaneous interactions with an enthalpy change (∆H0) of −1.79 ± 0.29 and −4.47 ± 0.51 kJ·mol−1 for ACV and PNV, respectively. The entropy change (∆S0) of 79.40 ± 0.95 and 69.95 ± 1.69 J·mol−1·K−1 for ACV and PNV, respectively, hence supported a potential contribution of electrostatic binding forces to the ACV-HSA and PNV-HSA systems. Putative binding of ACV/PNV to HSA, using previously reported site markers, showed that ACV/PNV were bound to HSA within subdomains IIA and IIIA (Sudlow sites I and II). Further confirmation was obtained through molecular docking studies of ACV-HSA and PNV-HSA binding, which confirmed the binding site of ACV/PNV with the most stable configurations of ACV/PNV within the HSA. These ACV/PNV conformers were shown to have free energies of −25.61 and −22.01 kJ·mol−1 for ACV within the HSA sites I and II and −22.97 and −26.53 kJ·mol−1 for PNV in HSA sites I and II, with hydrogen bonding and electrostatic forces being the main binding forces in such conformers.

Validated spectrometric determination of penciclovir and entecavir in bulk and in pharmaceutical preparations

Simple, rapid and sensitive spectroscopic methods were developed and validated for the determination of antiviral agents, namely, penciclovir (PCV) and entecavir (ETV). The first method is based on measuring the native fluorescence of each of the cited drugs at its optimum excitation and emission wavelengths. The fluorescence intensity was measured for PCV & ETV at 363nm and 370nm upon excitation at 260nm and 254nm, respectively. The calibration curves were linear over the concentration range 0.1–0.8, 0.025–0.4μgml−1 for PCV and ETV, respectively. The second method is based on measuring the amplitude of ETV in the fourth derivative with Δλ=8 and scaling factor=100 at 256.4nm at which its acidic degradation showed zero reading over the concentration range 5–60μgml−1. The proposed methods were applied for the determination of the cited drugs in bulk and pharmaceutical preparations. ICH guidelines were used for method validation.

Antiherpetic Plants: A Review of Active Extracts, Isolated Compounds, and Bioassays

Herpes simplex is a disease that is widely distributed throughout the world. It is caused by herpes simplex virus type 1 (HSV-1) and simplex virus type 2 (HSV-2). The drugs of choice for treatment are acyclovir (ACV), Penciclovir (PCV) and other guanine analogues, which have the same mechanism of action. However, due to the constant increase of ACV-resistant strains in immunocompromised patients, it is necessary to find new treatment alternatives. It has been shown that natural products are a good alternative for the treatment of these diseases as well as being an excellent source of compounds with anti-herpetic activity, which may be useful for the development of new drugs and act through a mechanism of action different from ACV and PCV. This paper compiles reports on extracts and compounds isolated from plants that have anti-herpetic activity. We present an analysis of the solvents most widely used for extraction from plants as well as cells and commonly used methods for evaluating cytotoxic and anti-herpetic activity. Families that have a higher number of plants with anti-herpetic activity are evaluated, and we also highlight the importance of studies of mechanisms of action of extracts and compounds with anti-herpetic activity.

Cutaneous biodistribution of ionizable, biolabile aciclovir prodrugs after short duration topical iontophoresis: Targeted intraepidermal drug delivery

The objective was to determine the cutaneous biodistribution of aciclovir (ACV), that is, the amount of drug as a function of depth within the skin following topical iontophoretic administration of amino acid ester prodrugs of ACV (ACV-X, where X=Arg, Ile or Val). The results were compared to those obtained with marketed formulations of aciclovir and penciclovir (PCV), and following topical iontophoresis of ACV. Quantification of molecules as a function of position in the skin was achieved by snap-freezing and cryotoming skin samples to obtain coarse or fine lamellae with a thickness of either 100μm or 20μm. The molecules – ACV, ACV-X or PCV – were extracted and quantified by validated UHPLC-MS/MS analytical methods. Passive delivery of ACV or PCV from marketed cream and ointment formulations after application for 60min resulted in modest cutaneous deposition (QDEP,ACV and QDEP,PCV<2nmol/cm2). Moreover, ACV and PCV were found mainly in the stratum corneum or superficial viable epidermis. The levels in the deeper skin layers (100–200μm), corresponding to the basal epidermis and adjacent area, where the virus would be found, were negligible. In contrast, iontophoresis of ACV-Ile or ACV-Arg for only 10min at 0.25mA/cm2 resulted in much greater deposition of ACV species at the same skin depths (100–200μm): for ACV-Ile – QDEP,ACV and QDEP,ACV-Ile were 17.2±6.9nmol/cm2 and 8.2±1.3nmol/cm2, respectively; in the case of ACV-Arg there was complete bioconversion and only ACV was recovered (QDEP,ACV was 41.2±9.2nmol/cm2). In the higher resolution biodistribution studies, with 20μm lamellae, short duration iontophoresis at 0.25mA/cm2 for only 5min of ACV-Arg or ACV-Ile still enabled considerable amounts of ACV species to be delivered to the basal epidermis and neighboring layers (QDEP,ACV was 4.0±1.6nmol/cm2 and 6.1±1.7nmol/cm2, respectively). Iontophoresis of ACV under the same conditions resulted in negligible ACV deposition in these layers. Subsequent studies into the iontophoresis of ACV-Ile using a hydrogel revealed no statistically significant differences between QDEP,ACV in full-thickness porcine and human skins (13.4±1.5nmol/cm2 and 12.4±1.4nmol/cm2, respectively), validating the porcine model. In order to improve ACV-Ile stability, dry fast dissolving thin film formulations were also prepared. These were placed in contact with conducting hydrogels in situ immediately prior to iontophoresis. In addition to the improved stability, iontophoretic delivery of ACV-Ile from the thin film was also superior to that from hydrogel alone. Following iontophoresis of ACV-Ile using fast dissolving films, QDEP,ACV was 29.1±1.0nmol/cm2, and the amount in the basal epidermis area was 2.7±0.1nmol/cm2. Short duration iontophoresis for 5min of ACV-Ile from aqueous solution, hydrogel or fast dissolving film resulted in supra-therapeutic concentrations of ACV in the basal epidermis and its adjacent area.

Synthesis, structural, conformational and DFT studies of N-3 and O-4 alkylated regioisomers of 5-(hydroxypropyl)pyrimidine

Because of the great pharmacological potential of the pyrimidine motif, novel C-5 substituted N-3 acyclic and O-4 acyclic pyrimidine derivatives were prepared as an interesting class of compounds for biological evaluation. Introduction of the 2,3-dihydroxypropyl (DHP) and penciclovir (PCV)-like side chains to 2-methoxypyrimidin-4-one (2) afforded a mixture of N- and O-acyclic pyrimidine nucleosides in the ratio of 54: 29 (3:4) and 57:21 (5:6) with N-3 isomer being dominant. Distinction between N- and O-alkylated pyrimidine moiety was deduced from extensive experimental FT-IR, HPLC-MS and 1D (1H, 13C) and 2D (COSY, HMQC and HMBC) NMR analyses. The N-, O-regioisomers were also examined by computational method at density functional theory (DFT) RB3LYP/6-31G(d), 6-31G∗∗ and 6-31+G∗ levels. DFT global chemical reactivity descriptors (total energy, chemical hardness, electronic chemical potential and electrophilicity) were calculated for the isomers and used to predict and describe their relative stability and reactivity. The chemical reactivity indices were related to the C2N3C4 bond angle. Theoretical predictions can be used to compare chemical reactivity and stability with future biological evaluation and behaviour of these compounds.

First enzymatic galactosylation of acyclic nucleoside drugs by β-galactosidase: Synthesis of water-soluble β-D-galactosidic prodrugs

Acyclic nucleoside analogs constitute an important group of antiviral agents. However, these nucleoside drugs suffer from poor water solubility and low oral bioavailability in the clinic use. In the present work, the enzymatic synthesis of the water-soluble galactosidic prodrugs of acyclic nucleosides by using bovine liver β-galactosidase was described. In the enzymatic transgalactosylation between acyclovir (ACV) and o-nitrophenyl β-galactopyranoside (oNPGal), the optimum enzyme dosage, buffer pH, temperature and molar ratio of ACV to oNPGal were 0.225 U/mL, 7.0, 40°C and 2.5, respectively, under which the initial reaction rate and the yield reached 0.40 mM/h and 29%, respectively. In addition, this enzyme could accept ganciclovir (GCV) and penciclovir (PCV) as substrates, affording the corresponding 4’-β-galactosylated derivatives with the yields of 26% and 71%, respectively.

Single nucleotide polymorphisms of thymidine kinase and DNA polymerase genes in clinical herpes simplex virus type 1 isolates associated with different resistance phenotypes

The role of mutations in the thymidine kinase (TK, UL23) and DNA polymerase (pol, UL30) genes of herpes simplex virus (HSV) for development of different resistance phenotypes has to be exactly determined before genotypic resistance testing can be implemented in patient’s care. Furthermore, the occurrence of cross-resistance is of utmost clinical importance. In this study, clinical HSV-1 isolates obtained between 2004 and 2011 from 26 patients after stem cell transplantation were examined in parallel by phenotypic and genotypic resistance testing. Thirteen isolates, which were phenotypically cross-resistant to acyclovir (ACV), penciclovir (PCV) and brivudin (BVDU), exhibited consistently frameshift or non-synonymous mutations in the TK gene known to confer resistance. One of these mutations (insertion of C at the nucleotide positions 1061–1065) has not been described before. Seven strains, phenotypically resistant to ACV and PCV and, except one each, sensitive to BVDU and resistant to foscarnet (FOS), carried uniformly resistance-related substitutions in the DNA pol gene. Finally, 3 isolates, resistant to ACV, PCV and 2 out of these also resistant to BVDU, had known but also unclear substitutions in the TK and DNA pol genes, and 3 isolates were completely sensitive. In conclusion, clinical ACV-resistant HSV-1 isolates, carrying resistance-associated mutations in the TK gene, can be regarded as cross-resistant to other nucleoside analogs such as BVDU. In contrast, clinical FOS-resistant HSV-1 strains which are cross-resistant to ACV may be sensitive to BVDU. This has to be considered for drug changes in antiviral treatment in case of ACV resistance.

Accelerated effect on Mitsunobu reaction via bis-N-tert-butoxycarbonylation protection of 2-amino-6-chloropurine and its application in a novel synthesis of penciclovir

Solubility of 2-amino-6-chloropurine in Mitsunobu solvents could be significantly improved after its exocyclic amino group is protected via N-tert-butoxycarbonylation. The bis-Boc protected 2-amino-6-chloropurine also shows excellent activity and N9 selectivity in the coupling with various alcohols by a Mitsunobu reaction. Then, a new practical and efficient method is established for the synthesis of penciclovir (PCV) from bis-Boc-2-amino-6-chloropurine 9 and the side chain of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxane 5—the latter being a more easily prepared cyclic precursor of the diacetate side chain used in the conventional process. The coupling of 9 with 5 proceeded regioselectively at a N9 position of purine derivative for a good yield under Mitsunobu conditions.

Update On Emerging Antivirals For The Management Of Herpes Simplex Virus Infections: A Patenting Perspective

Herpes simplex virus (HSV) infections can be treated efficiently by the application of antiviral drugs. The herpes family of viruses is responsible for causing a wide variety of diseases in humans. The standard therapy for the management of such infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valaciclovir and famciclovir. Though effective, long term prophylaxis with the current drugs leads to development of drug-resistant viral isolates, particularly in immunocompromised patients. Moreover, some drugs are associated with dose-limiting toxicities which limit their further utility. Therefore, there is a need to develop new antiherpetic compounds with different mechanisms of action which will be safe and effective against emerging drug resistant viral isolates. Significant advances have been made towards the design and development of novel antiviral therapeutics during the last decade. As evident by their excellent antiviral activities, pharmaceutical companies are moving forward with several new compounds into various phases of clinical trials. This review provides an overview of structure and life cycle of HSV, progress in the development of new therapies, update on the advances in emerging therapeutics under clinical development and related recent patents for the treatment of Herpes simplex virus infections. Keywords: Emerging therapeutics, infections life cycle, Herpes simplex virus, recent patents, treatment, Viral Entry, ANTI-HSV DRUGS, sacral ganglia, Valomaciclovir, Fusion Peptidic Inhibitors