Antiherpetic activity of a sulfated polysaccharide from Agaricus brasiliensis mycelia

Sulfated polysaccharides are good candidates for drug discovery in the treatment of herpetic infections. Agaricus brasiliensis (syn A. subrufescens, A. blazei) is a Basidiomycete fungus native to the Atlantic forest region of Southeastern Brazil. Herein we report the chemical modification of a polysaccharide extracted from A. brasiliensis mycelia to obtain its sulfated derivative (MI-S), which presented a promising inhibitory activity against HSV-1 [KOS and 29R (acyclovir-resistant) strains] and HSV-2 strain 333, with selectivity indices (SI = CC₅₀/IC₅₀) higher than 439, 208, and 562, respectively. The mechanisms underlying this inhibitory activity were scrutinized by plaque assay with different methodological strategies. MI-S had no virucidal effects, but inhibited HSV-1 and HSV-2 attachment, penetration, and cell-to-cell spread, as well as reducing the expression of HSV-1 ICP27, UL42, gB, and gD proteins. MI-S also presented synergistic antiviral effect with acyclovir. These results suggest that MI-S presents multiple modes of anti-HSV action.     

The tolerance to and pharmacokinetics of penciclovir (BRL 39123A), a novel antiherpes agent,administered by intravenous infusion to healthy subjects

Summary The tolerance to and pharmacokinetics of intravenously administered penciclovir (BRL 39123A), a novel anti-herpes agent, were investigated in 15 healthy male subjects. The volunteers were divided into three groups, receiving either 10, 15 or 20 mg/kg penciclovir by a 60 min constant-rate infusion. Blood samples were taken sequentially up to 48 h after the start of the infusion and urine collections made at appropriate intervals up to 72 h. After a simple solid phase extraction, concentrations of penciclovir in plasma and urine were determined using HPLC with U. V detection.Mean values of C_max, corresponding usually with the end of infusion, and of AUC appeared to increase proportionately with dose. Furthermore, there was no evidence that dose significantly affected any individual pharmacokinetic parameter.Penciclovir was distributed into tissues with an overall mean volume of distribution of approximately 1.51 · kg^–1, i. e. approximately double that of body water. It was rapidly eliminated, with a mean total plasma clearance of 39.31 · h^–1, and a mean terminal-phase half-life of 2.0 h. The majority of the dose, approximately 70%, was excreted unchanged in the urine. Mean renal clearance of BRL 39123 was 28.1 1 · h^–1, which exceeds normal glomerular filtration rate and approaches renal plasma flow.At all dose-levels, the infusions of penciclovir were well tolerated, with no evidence of drug-related adverse events.     

Antiherpes activity of glucoevatromonoside, a cardenolide isolated from a Brazilian cultivar of Digitalis lanata

Cardiac glycosides, known ligands of the sodium pump, are widely used in the treatment of heart failure, such as digoxin and digitoxin. Besides this important activity, other biological activities, such as the antiviral activity, have been described for this group. HSV are responsible for many infections of oral, ocular and genital regions. Treatment with nucleoside analogs such as acyclovir is effective in most cases; however drug-resistance may arise due to prolonged treatment mainly in immunocompromised individuals. In this study, an antiherpes screening was performed with 65 cardenolide derivatives obtained from different sources, and one natural cardenolide, glucoevatromonoside, inhibited HSV-1 and HSV-2 replication at very low concentrations. This cardenolide showed viral inhibitory effects if added up to 12 h p.i. and these effects appear to take place by the inhibition of viral proteins synthesis (ICP27, U_L42, gB, gD), the blockage of virus release and the reduction of viral cell-to-cell spread. This compound also showed synergistic antiviral effects with acyclovir and anti-Na⁺K⁺ATPase activity, suggesting that cellular electrochemical gradient alterations might be involved in the mechanism of viral inhibition. These results suggest that cardenolides might be promising for future antiviral drug design.     

腺嘌呤衍生物的合成及体外抗疱疹病毒活性

以腺嘌呤为母体,在其9位引入活性基团N-取代缩氨基硫脲(TSC),设计合成了12个6-氨基-9(N^4'-取代乙醛缩氨基硫脲)嘌呤衍生物(4a～1),并进行了体外抗单纯疱疹病毒I型(HSV-1),II型(HSV-2),水痘-带状疱疹病毒(VZV)活性试验及细胞毒性试验。结果表明,除化合物4e及4f对HSV-1及VZV有较高活性外,其余化合物对上述两种病毒的活性均不明显。另外,将4e与4f分别与无环鸟苷(ACV)联合用药,其最小抑制浓度(MIC)及细胞毒性(MCC)均显著下降。     

Antimutagenic and antiherpetic activities of different preparations from Uncaria tomentosa (cat’s claw)

Uncaria tomentosa have been used to treat viral diseases such as herpes due to multiple pharmacological effects, but its therapeutic efficacy against this virus have not been reported yet. Thus, in vitro antiherpetic activity of hydroethanolic extract from barks, purified fractions of quinovic acid glycosides and oxindole alkaloids was evaluated by plaque reduction assay, including mechanistic studies (virucidal, attachment and penetration action). Once exposure to physical agents might lead to reactivation of the herpetic infection, antimutagenic effect (pre-, simultaneous and post-treatment protocols) was also evaluated by Comet assay. The antiherpetic activity from the samples under investigation seemed to be associated with the presence of polyphenols or their synergistic effect with oxindole alkaloids or quinovic acid glycosides, once both purified fractions did not present activity when evaluated alone. Inhibition of viral attachment in the host cells was the main mechanism of antiviral activity. Although both purified fractions displayed the lowest antimutagenic activity in pre and simultaneous treatment, they provided a similar effect to that of cat’s claw hydroethanolic extract in post-treatment. Given that purified fractions may result in a reduced antiherpetic activity, the use of cat’s claw hydroethanolic extract from barks should be prioritized in order to obtain a synergistic effect.     

Synthesis and biological activity of 5-hydroxy-4-quinolones and 5-methoxy-4-quinolones as truncated acridones

A series of 5-hydroxy-4-quinolone (3) and 5-methoxy-4-quinolone (4) derivatives were synthesized as truncated acridone analogues and evaluated for antitumor, antiherpes and antituberculosis activities. Among them 5-hydroxy-8-methoxy-quinolone showed potent antitumor activity (IC₅₀=17.7 μM for HL60) which was greater than that of acronycine. However, these compounds didn't show any significant antiherpes or antituberculosis activity.