Antiherpetic Drugs Research Articles

Combined effect of basic antiherpetic drugs with a new inhibitor of the terminase complex of herpes simplex virus type 1 in Vero cell culture

More than 90% of the world’s population are carriers of herpes simplex virus type 1 (HSV-1). The infection manifests itself in the formation of blisters and ulcers on the face or genitals, and can cause blindness, encephalitis, and generalized infection. All modern first- and second-line 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 described earlier, uses the large subunit of the HSV-1 terminase complex as a biotarget and selectively inhibits its reproduction in vitro. For the first time, we have obtained fundamentally new results on the combined effect of LAS-131 on human herpesvirus infection with practically significant antiviral compounds – nucleoside analogues (acyclovir [ACV], penciclovir [PCV], ganciclovir [GCV], brivudine [BVDU], iododeoxyuridine [IDU], adenine arabinoside [Ara-A], as well as a nucleoside phosphonate analogue (cidofovir [CDV]) and a pirophosphate analogue (foscarnet [FOS]). Using a inhibition assay of cytopathic effect (CPE) induced by a virus, it was shown that when combined with LAS-131, the concentrations of the compounds in combinations providing inhibition of HSV-1-induced CPE by 50%, decreased by 2 times (additive effect, FOS) or more (synergistic effect, ACV, PCV, GCV, IDU, BVDU, Ara-A, CDV). Reducing the concentrations of agents creates non-permissive conditions for the reproduction of HSV-1 and opens up new real possibilities for controlling human herpesvirus infection.

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.

Rational approaches to therapy for combined urogenital infections in married couples

The purpose of the study. The aim of the study was to evaluate the effectiveness of antiviral therapy in urogenital infection caused by the herpes simplex virus in combination with human papillomavirus (HSV‑1, -2 and HPV) in couples with impaired reproductive function.Materials and methods. The study included 149 married couples with complaints about the absence or pathological course of pregnancy with termination in the first trimester. Urogenital infection caused by the herpes simplex virus was detected in 80 couples. A combination with human papillomavirus was detected in 36 cases. The effectiveness of antiviral therapy was evaluated.Results. After the first course of treatment with the use of an antiherpetic drug in 80 couples who had manifestations of active herpes infection, pregnancy and the birth of a healthy child were registered in 44 cases (55%). Combination therapy with acyclovir or valacyclovir and inosine pranobex was required, which led to a positive dynamic of indicators in case of a combined infection. The onset and normal course of pregnancy were registered after treatment in 33% of couples in this group.Conclusions. A possible cause of reproductive dysfunction with the absence or termination of pregnancy in the early stages may be a urogenital infection caused by HSV types 1, 2. In most cases, antiviral therapy promotes the birth of a healthy child. The ineffectiveness of therapy may be associated with the simultaneous presence of two or more infectious significant agents. For the treatment of couples who have an active persistence of HSV‑1, -2 in combination with HPV, the appointment of inosine pranobex in combination with acyclovir or valacyclovir is recommended.

Prospects for the use of Lipster Mint cream in the complex treatment of herpes zoster

Objective — to investigate the clinical efficacy of Lipster Mint cream in the complex treatment of patients with herpes zoster. 
 Materials and methods. The study included 15 patients (11 women and 4 men) with acute herpes zoster. The age of the patients ranged from 38 to 70 years. The patients had severe clinical symptoms (typical vesicular rash, itching of varying intensity, burning sensation, intense pain along the affected nerves and sleep disturbance). The localization of pathological foci was unilateral: in 12 patients on the skin of the trunk, in 1 patient on the buttock and in 2 patients on the skin of the thigh. All patients reported a decrease in quality of life due to the disease. The complex treatment included Valavir, one of the valacyclovir drugs, according to the recommended regimens, which was administered orally in 1000 mg tablets three times a day for 7 days. Acute herpes-associated pain and heartburn were relieved with analgesics and topical application of Lipster Mint cream, manufactured by Farmak (Ukraine), which contains acyclovir 5 % and menthol. A distinctive advantage of Lipster Mint is that it contains the highest dose of acyclovir permitted for topical products — 5 %, as well as menthol which cools and reduces itching. The effectiveness of treatment of herpes zoster was assessed by the dynamics of clinical symptoms and subjective feelings on the 2nd, 5th and 10th days of treatment. 
 Results and discussion. As a result of the treatment, positive dynamics of all clinical manifestations was achieved. Inflammatory phenomena such as swelling and hyperemia of the skin significantly decreased, the appearance of fresh herpes rash stopped within 24 hours, body temperature normalized on the 2—3rd day, general condition improved, pain and discomfort in the affected areas significantly decreased, partial epithelialization of erosions and the appearance of crusts were observed on the 5—7th day. With the topical application of Lipster Mint, under the influence of menthol, from the first minutes of application, patients significantly reduced the sensations of burning, tingling and pain in the areas of skin lesions. 
 Conclusions. Despite the available arsenal of specific and non-specific antiherpetic drugs, treatment of patients suffering from herpes zoster continues to be an urgent medical problem that requires further improvement and individualized approach. Our clinical observations indicate the effectiveness of the systemic drug Valavir and the topical drug Lipster Mint cream in the complex treatment of herpes zoster, which makes it possible to reduce postherpetic neuralgia in the areas of skin lesions and improve the quality of life of patients.

Enhanced Anti-Herpetic Activity of Valacyclovir Loaded in Sulfobutyl-ether-β-cyclodextrin-decorated Chitosan Nanodroplets.

Valacyclovir (VACV) was developed as a prodrug of the most common anti-herpetic drug Acyclovir (ACV), aiming to enhance its bioavailability. Nevertheless, prolonged VACV oral treatment may lead to the development of important side effects. Nanotechnology-based formulations for vaginal administration represent a promising approach to increase the concentration of the drug at the site of infection, limiting systemic drug exposure and reducing systemic toxicity. In this study, VACV-loaded nanodroplet (ND) formulations, optimized for vaginal delivery, were designed. Cell-based assays were then carried out to evaluate the antiviral activity of VACV loaded in the ND system. The chitosan-shelled ND exhibited an average diameter of about 400 nm and a VACV encapsulation efficiency of approximately 91% and was characterized by a prolonged and sustained release of VACV. Moreover, a modification of chitosan shell with an anionic cyclodextrin, sulfobutyl ether β-cyclodextrin (SBEβCD), as a physical cross-linker, increased the stability and mucoadhesion capability of the nanosystem. Biological experiments showed that SBEβCD-chitosan NDs enhanced VACV antiviral activity against the herpes simplex viruses type 1 and 2, most likely due to the long-term controlled release of VACV loaded in the ND and an improved delivery of the drug in sub-cellular compartments.

Real-world safety and efficacy of amenamevir in patients with herpes zoster in Japan: A postmarketing observational study (REWARD).

The helicase-primase inhibitor amenamevir (AMNV) was approved for herpes zoster in Japan in 2017. The authors conducted a 1-month postmarketing observational study to evaluate the real-world safety and efficacy (cutaneous improvement and pain resolution) of AMNV in patients with herpes zoster. Of the 3453 patients registered between March 2018 and December 2020, 3110 were included in the safety analyses. The mean age (±standard deviation) was 63.7 ± 17.5 years, with 57.9% of patients aged ≥65 years. Most patients had mild (53.3%) or moderate (41.0%) cutaneous lesions. Regarding pain, 43.9%, 25.6%, and 12.5% of patients had pain at the levels of 1-3, 4-6, and 7-10 on the numerical rating scale. In total, 30.0%, 27.2%, and 16.1% of patients were concomitantly treated with analgesics: acetaminophen, nonsteroidal anti-inflammatory drugs, and Ca2+ channel α 2δ ligands, respectively, and 10.6% were treated with topical antiherpetic drugs. Adverse drug reactions occurred in 0.77% of patients, including four serious adverse drug reactions in four patients (hyponatremia, thrombocytopenia, rash, and rhabdomyolysis). Regarding important potential risks, renal disorder, cardiovascular events, and decreased platelets were observed in one, one, and two patients, respectively. Concerning efficacy, the cutaneous improvement rate (significantly improved or improved) was 95.5%, with significantly higher improvement rates in patients treated with AMNV for 7 days and in patients with less severe cutaneous lesions or less pain. Factors affecting the time to pain resolution were the severity of cutaneous lesions and pain at the start of AMNV treatment and older age. This study demonstrated that the AMNV is safe and effective in patients with herpes zoster in a real-world clinical setting.

Suchasni zasady likuvannia henitalnoho herpesu u zhinok (ohliad literatury; rezultaty vlasnykh doslidzhen)

Introduction. Recently, much attention has been paid to the problem of new approaches in the treatment of genital herpes in women. The problem is extremely important, because this genital infection is very common in the world. The main types of genital infection are herpes simplex virus (HSV-1) and (HSV-2). Worldwide, more than 400 million people have genital herpes caused by HSV-2. In the United States of America (USA), nearly one in five adults (approximately 40 million people) have HSV-2 infection, with approximately one million new infections occurring each year. The aim of the study. To analyze the modern principles of treatment of genital herpes in women, using literary sources and the results of own research. Materials and methods. In total, twelve publications by foreign authors were selected and processed based on their relevance to the chosen topic, and information on the effectiveness of the use of the antiviral agent “Virostat” in one’s own practice was provided. Results. To date, there are several strategies for the use of antiherpetic drugs (acyclovir, virostat (famciclovir), valacyclovir), which have been studied and tested in cases of first infection with genital herpes, episodic and suppressive cure. There are two important priorities for the treatment of genital herpes: the first is to prevent clinical manifestations and relapses, and the second is to prevent transmission to sexual partners. Our clinical experience allows us to recommend the use of the Ukrainian medicine “Virostat” (producer “Kyiv Vitamin Plant”) for the treatment of HSV infection in women with various clinical manifestations. Conclusions. To date, it should be noted that genital herpes remains a very common sexually transmitted disease. The increasing frequency of HSV-1 and HSV-2 is associated with recurrences of genital ulcer disease. HSV-2 plays a key role in the spread of HIV and, although rare, HSV-1 and HSV-2 lead to severe complications if contracted during pregnancy, both among mothers and newborns. A review of the literature on the treatment of sexually transmitted diseases as of 2021 found few significant advances in the treatment of genital herpes infections. The greater availability of nucleic acid amplification tests for the diagnosis of HSV in the presence of genital ulcers improves diagnosis in the acute phase, but serological tests lack diagnostic accuracy, so advances in the diagnostic algorithm as well as new diagnostic tools are needed. Although the symptoms of genital herpes can be controlled and transmission to sexual partners can be prevented with antiviral therapy, new treatments with new mechanisms of action will improve the well-being of patients. Considering our clinical experience of using the Ukrainian medicine “Virostat” for various clinical manifestations, we recommend its wide implementation and use.

Investigating the Safety and Efficacy of the Synthetic Drug Herbix on Immune Responses Involved in the Treatment of a Mouse Model of Herpes Simplex Virus.

Herpes simplex virus-1 (HSV-1) infections can cause significant harm to individuals, including blindness, congenital defects, genital herpes, and even cancer, with no definitive cure .so, finding new treatment strategies is crucial. In this study, 25 male BALB/c mice were used to conduct a mouse model of herpes by subcutaneously injecting an HSV-1 suspension (100 µL of 1× PFU/mL). The mice were divided into 5 groups with groups 1 to 3 designated as intervention groups, and groups 4 and 5 serving as positive and negative control groups, respectively. After 2 days of virus inoculation, the mice were treated with different concentrations of Herbix (100, 200, and 300 mg/mL) via subcutaneous injection. Mice Blood samples (0.5 to 1 mL) were taken from the mice before and after the experiments, and after three-week follow-up period, the mice were sacrificed and the spleens were removed for lymphocyte analysis. we found that administration of Herbix at a dose of 300 mg/mL showed the greatest efficacy, characterized by a delay in skin lesion formation, an increment in survival rate and lymphocyte proliferation, upregulation of the gene expression of interferon alpha (IFN-α) and tumor necrosis factor alpha (TNF-α), and an increase in the polarization of cytotoxic and helper T lymphocytes compared to the control group. These results suggest that Herbix at a dose of 300 mg/mL is effective in treating murine herpes and stimulating immune responses, making it a potential candidate for further investigation as an antiherpetic drug.

Antiherpetic Activity of Carrageenan Complex with Echinochrome A and Its Liposomal Form.

Herpes simplex virus (HSV) infections, the incidence of which is still widespread throughout the world, are actualizing the search and development of new, more effective antiherpetic drugs. The development of multifunctional drug delivery systems, including liposome-based ones, has become a relevant and attractive concept in nanotechnology. The ability of complexes of κ- and Σ-carrageenans (CRGs)-sulfated polysaccharides of red algae, with echinochrome A (Ech), as well as the liposomal form of the Σ-CRG/Ech complex-to inhibit different stages of HSV-1 infection in Vero cells was studied. By quantum chemical calculations, it was shown that CRG forms stable complexes with Ech. We have shown that complexes of κ-CRG/Ech and Σ-CRG/Ech exhibit highest virucidal activity with a selectivity index (SI) of 270 and 350, respectively, and inhibition of virus-cell interaction (SI of 83 and 32, respectively). The liposomal form of the Σ-CRG/Ech complex after virus adsorption and penetration to cells effectively reduced the HSV-1 plaque formation. The virus-inhibiting activity of the liposomal form of the Σ-CRG/Ech complex was three times higher than that of the Σ-CRG/Ech complex itself. Obtaining CRGs/Ech complexes and their liposomal forms can become the basis of a successful strategy for the development of promising antiherpetic drugs.

Герпетические заболевания глаз в условиях пандемии, вызванной коронавирусом COVID-19

Purpose.To highlight the data of scientific papers on the development of herpes eye diseases in patients with COVID-19 and after vaccination against this infection. Material and methods. To complete the review, we searched for literature sources in the PubMed and Scopus reference databases for the period from 2019 to 2022 using the keywords «herpesvirus eye infection covid-19», «herpes virus eye infection, vaccination for COVID-19». In total, 30 articles were selected that relate to the topic of the review. Discussion. According to some researchers, SARS-CoV-2 infection may be a risk factor for the development and reactivation of herpes viruses, which is much more common in invasively ventilated patients with COVID-19. Indirectly, this is evidenced by the growth in the number of patients with ophthalmic herpes during the COVID-19 pandemic around the world. The literature also discusses cases of development or recurrence of ophthalmic herpes after the use of various types of vaccines. While there are various assumptions of their occurrence, one of them seems to be related to the stimulation of the immune system after vaccination and the activation of a strong T-cell response, which allows viruses to emerge from the latent phase, which requires scientific research. Conclusion. The literature review suggests that, according to the studies published to date, COVID-19 can be a potential activator of HSV-1 infection, and, accordingly, become a risk factor for the development of ophthalmic herpes. Therefore, patients with COVID-19 are advised to prescribe antiherpetic drugs as additional therapy. Key words: covid-19, herpes eye infection, COVID-19, vaccination

A proof-of-concept study for the efficacy of dispirotripiperazine PDSTP in a rabbit model of herpes simplex epithelial keratitis

Herpes simplex keratitis is an important infectious cause of blindness worldwide. The mainstay of antiviral therapy is treatment with long-established nucleoside analogues orally or topically. However, the emergence of resistant strains may become a major health concern in the future. Therefore, the development of backup antiherpetic medicines is urgently needed. Small molecule PDSTP is known to be active against herpes simplex type 1 strains in vitro, affecting early host-pathogen interactions. Here, we evaluated its preclinical efficacy in a rabbit model of herpes simplex epithelial keratitis. The mean course of keratitis and the corneal lesions in the 1.0% PDSTP gel group was statistically significantly less than in the negative control group and was comparable to that in the aciclovir group. These findings open up new opportunities for the development of antiherpetic drugs with an original mechanism of action.

Клинический случай острого иридоциклита на фоне неспецифического язвенного колита

Conducting adequate therapy for iridocyclitis (uveitis) remains an urgent problem in patients with ulcerative colitis (UC) due to the development of this complication in almost every fifth of them. Purpose. To present a clinical case of acute iridocyclitis (AI) in a patient with UC after suffering an acute respiratory disease (ARI) accompanied by a recurrence of Herpes labialis. Material and methods. Examination of a patient at the stage of remission of UC, who applied on the 5th day of the disease with a clinic of acute iridocyclitis and Herpes labialis after acute respiratory infections, suggested an etiological or trigger role of the herpes simplex virus in the development of inflammation in the choroid. Results. Conducting complex therapy with the inclusion of the drug valaciclovir led to the relief of clinical symptoms of OI already on the 16th day of the disease and increased visual acuity. Conclusion. Supplementing the treatment of acute iridocyclitis, which developed against the background of a relapse of a latent herpes infection in a patient with chronic UC in remission, with an antiherpetic drug is etiopathogenetically substantiated to achieve good visual results. Key words: acute iridocyclitis, nonspecific ulcerative colitis, herpes infection

Variations in Aspects of Neural Precursor Cell Neurogenesis in a Human Model of HSV-1 Infection

ABSTRACT Encephalitis, the most significant of the central nervous system (CNS) diseases caused by Herpes simplex virus 1 (HSV-1), may have long-term sequelae in survivors treated with acyclovir, the cause of which is unclear. HSV-1 exhibits a tropism toward neurogenic niches in CNS enriched with neural precursor cells (NPCs), which play a pivotal role in neurogenesis. NPCs are susceptible to HSV-1. There is a paucity of information regarding the influence of HSV-1 on neurogenesis in humans. We investigated HSV-1 infection of NPCs from two individuals. Our results show (i) HSV-1 impairs, to different extents, the proliferation, self-renewing, and, to an even greater extent, migration of NPCs from these two subjects; (ii) The protective effect of the gold-standard antiherpetic drug acyclovir (ACV) varies with viral dose and is incomplete. It is also subject to differences in terms of efficacy of the NPCs derived from these two individuals. These results suggest that the effects of HSV-1 may have on aspects of NPC neurogenesis may vary among individuals, even in the presence of acyclovir, and this may contribute to the heterogeneity of cognitive sequelae across encephalitis survivors. Further analysis of NPC cell lines from a larger number of individuals is warranted.

40 Years after the Registration of Acyclovir: Do We Need New Anti-Herpetic Drugs?

Herpes simplex virus types 1 and 2 HSV1 and 2, namely varicella-zoster VZV and cytomegalovirus CMV, are among the most common pathogens worldwide. They remain in the host body for life. The course of infection with these viruses is often asymptomatic or mild and self-limiting, but in immunocompromised patients, such as solid organ or bone marrow transplant recipients, the course can be very severe or even life-threatening. Unfortunately, in the latter group, the highest percentage of infections with strains resistant to routinely used drugs is observed. On the other hand, frequent recurrences of genital herpes can be a problem even in people with normal immunity. Genital herpes also increases the risk of acquiring sexually transmitted diseases, including HIV infection and, if present in pregnant women, poses a risk to the fetus and newborn. Even more frequently than herpes simplex, congenital infections can be caused by cytomegalovirus. We present the most important anti-herpesviral agents, the mechanisms of resistance to these drugs, and the associated mutations in the viral genome. Special emphasis was placed on newly introduced drugs such as maribavir and brincidofovir. We also briefly discuss the most promising substances in preclinical testing as well as immunotherapy options and vaccines currently in use and under investigation.

The Peptide A-3302-B Isolated from a Marine Bacterium Micromonospora sp. Inhibits HSV-2 Infection by Preventing the Viral Egress from Host Cells.

Herpesviruses are highly prevalent in the human population, and frequent reactivations occur throughout life. Despite antiviral drugs against herpetic infections, the increasing appearance of drug-resistant viral strains and their adverse effects prompt the research of novel antiherpetic drugs for treating lesions. Peptides obtained from natural sources have recently become of particular interest for antiviral therapy applications. In this work, we investigated the antiviral activity of the peptide A-3302-B, isolated from a marine bacterium, Micromonospora sp., strain MAG 9-7, against herpes simplex virus type 1, type 2, and human cytomegalovirus. Results showed that the peptide exerted a specific inhibitory activity against HSV-2 with an EC50 value of 14 μM. Specific antiviral assays were performed to investigate the mechanism of action of A-3302-B. We demonstrated that the peptide did not affect the expression of viral proteins, but it inhibited the late events of the HSV-2 replicative cycle. In detail, it reduced the cell-to-cell virus spread and the transmission of the extracellular free virus by preventing the egress of HSV-2 progeny from the infected cells. The dual antiviral and previously reported anti-inflammatory activities of A-3302-B, and its effect against an acyclovir-resistant HSV-2 strain are attractive features for developing a therapeutic to reduce the transmission of HSV-2 infections.

Antiherpetic drugs: a potential way to prevent Alzheimer\u2019s disease?

BackgroundConsidering the growing body of evidence suggesting a potential implication of herpesviruses in the development of dementia, several authors have questioned a protective effect of antiherpetic drugs (AHDs) which may represent a new means of prevention, well tolerated and easily accessible. Subsequently, several epidemiological studies have shown a reduction in the risk of dementia in subjects treated with AHDs, but the biological plausibility of this association and the impact of potential methodological biases need to be discussed in more depth.MethodsUsing a French medico-administrative database, we assessed the association between the intake of systemic AHDs and the incidence of (i) dementia, (ii) Alzheimer’s disease (AD), and (iii) vascular dementia in 68,291 subjects over 65 who were followed between 2009 and 2017. Regarding potential methodological biases, Cox models were adjusted for numerous potential confounding factors (including proxies of sociodemographic status, comorbidities, and use of healthcare) and sensitivity analyses were performed in an attempt to limit the risk of indication and reverse causality biases.Results9.7% of subjects (n=6642) had at least one intake of systemic AHD, and 8883 incident cases of dementia were identified. Intake of at least one systemic AHD during follow-up was significantly associated with a decreased risk of AD (aHR 0.85 95% confidence interval [0.75–0.96], p=0.009) and, to a lesser extent with respect to p values, to both dementia from any cause and vascular dementia. The association with AD remained significant in sensitivity analyses. The number of subjects with a regular intake was low and prevented us from studying its association with dementia.ConclusionsTaking at least one systemic AHD during follow-up was significantly associated with a 15% reduced risk of developing AD, even after taking into account several potential methodological biases. Nevertheless, the low frequency of subjects with a regular intake questions the biological plausibility of this association and highlights the limits of epidemiological data to evaluate a potential protective effect of a regular treatment by systemic AHDs on the incidence of dementia

The Valproic Acid Derivative Valpromide Inhibits Pseudorabies Virus Infection in Swine Epithelial and Mouse Neuroblastoma Cell Lines.

Pseudorabies virus (PRV) infection of swine can produce Aujeszky’s disease, which causes neurological, respiratory, and reproductive symptoms, leading to significant economic losses in the swine industry. Although humans are not the natural hosts of PRV, cases of human encephalitis and endophthalmitis caused by PRV infection have been reported between animals and workers. Currently, a lack of specific treatments and the emergence of new PRV strains against which existing vaccines do not protect makes the search for effective antiviral drugs essential. As an alternative to traditional nucleoside analogues such as acyclovir (ACV), we studied the antiviral effect of valpromide (VPD), a compound derived from valproic acid, against PRV infection in the PK15 swine cell line and the neuroblastoma cell line Neuro-2a. First, the cytotoxicity of ACV and VPD in cells was compared, demonstrating that neither compound was cytotoxic at a specific concentration range after 24 h exposure. Furthermore, the lack of direct virucidal effect of VPD outside of an infected cell environment was demonstrated. Finally, VPD was shown to have an antiviral effect on the viral production of two strains of pseudorabies virus (wild type NIA-3 and recombinant PRV-XGF) at the concentrations ranging from 0.5 to 1.5 mM, suggesting that VPD could be a suitable alternative to nucleoside analogues as an antiherpetic drug against Aujeszky’s disease.

Anti‐herpetic drugs: A potential way to prevent Alzheimer’s disease?

AbstractBackgroundConsidering the potential implication of Herpes viruses in the development of dementia, anti‐herpetic drugs (AHD) may represent a new means of prevention.MethodUsing a medico‐administrative database, we assessed the association between the intake of systemic AHD and the incidence of i) dementia, ii) Alzheimer’s disease (AD) and iii) vascular dementia (VaD) among 68 291 participants over 65 followed between 2009 and 2017. Cox models using systemic AHD as time‐dependent variable were adjusted for age, sex, being beneficiary of a complementary health insurance scheme for low‐income people, the presence of several co‐morbidities (hypertension, diabetes, hypercholesterolemia, stroke, heart diseases), the intake of anti‐inflammatory drugs, the number of consultations, and the number of different medications the year before inclusion.Result9.7% of the participants (n=6642) had at least one intake of systemic AHD and 8883 incident dementia were identified. The intake of at least one systemic AHD was significantly associated to a decreased risk of AD (aHR 0.85 95% confidence interval [0.75‐0.96], p=0.009) and, to a lesser extent regarding p‐values, to both dementia any cause (aHR 0.90 [0.82‐0.99], p=0.03) and VaD (aHR 0.80 [0.65‐0.995], p=0.045). As the percentage of participants with a regular intake was very low (among those with at least one intake of systemic AHD, the median number of deliveries per year of follow‐up was 0.12), the efficacy of regular intake of AHD could not be evaluated.ConclusionTaking at least one systemic AHD during follow‐up was significantly associated to a risk reduced by 15% of developing AD. Despite the low percentage of participants with a regular intake during the follow‐up, this association may reflect a protective impact of systemic AHD on the prevention of dementia in particular considering the possibility of more regular treatment in the period preceding the inclusion. It also highlights the limitations of medico‐administrative databases to assess the efficacy of a regular intake of systemic AHD given their current use in clinical practice. Thus, given the growing body of evidence supporting the infectious hypothesis, preventive clinical trials with prolonged treatment by systemic AHD are urgently needed.

Characteristics of Helicase-Primase Inhibitor Amenamevir-Resistant Herpes Simplex Virus.

The antiherpetic drug amenamevir (AMNV) inhibits the helicase-primase complex of herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus directly as well as inhibiting the replication of these viruses. Although several mutated HSV viruses resistant to helicase-primase inhibitors have been reported, the mutations contributing to the resistance remain unclear, as recombinant viruses containing a single mutation have not been analyzed. We obtained AMNV-resistant viruses with amino acid substitutions by several passages under AMNV treatment. Twenty HSV-1 and 19 HSV-2 mutants with mutation(s) in UL5 helicase and/or UL52 primase, but not in cofactor UL8, were isolated. The mutations in UL5 were located downstream of motif IV, with UL5 K356N in HSV-1 and K355N in HSV-2, in particular, identified as having the highest frequency, which was 9/20 and 9/19, respectively. We generated recombinant AMNV-resistant HSV-1 with a single amino acid substitution using bacterial artificial chromosome (BAC) mutagenesis. As a result, G352C in UL5 helicase and F360C/V and N902T in UL52 primase were identified as novel mutations. The virus with K356N in UL5 showed 10-fold higher AMNV resistance than did other mutants and showed equivalent viral growth in vitro and virulence in vivo as the parent HSV-1, although other mutants showed attenuated virulence. All recombinant viruses were susceptible to the other antiherpetic drugs, acyclovir and foscarnet. In conclusion, based on BAC mutagenesis, this study identified, for the first time, mutations in UL5 and UL52 that contributed to AMNV resistance and found that a mutant with the most frequent K356N mutation in HSV-1 maintained viral growth and virulence equivalent to the parent virus.

Intracellular ways of development of Alzheimer's disease against the background of herpes viral infections (literature review)

The concept of the viral etiology of Alzheimer's disease (AD) was first proposed in 1982. Its author MJ Ball suggested that the herpes simplex virus (HSV1) may be involved in the pathogenesis of AD, finding that the areas of the brain damaged in acute herpetic encephalitis are the same as those that are affected in AD, and those who survived usually suffer from memory loss and other cognitive impairment typical of AD. Subsequently, in all postmortem brain samples (temporal, frontal, and hippocampal) viral sequences of the viral thymidinekinase gene were found in a high proportion (70-100%) both in AD and in elderly people without it, while in young people and children the virus was found in very low proportions, so it was suggested that HSV1 comes from the peripheral ganglia, where the virus can remain inactive for many years, then enters the brain at an older age due to a decrease in the activity of the immune system. The increased risk of AD is associated with the presence of HSV1 in the brain and the carriage of a specific genetic factor – allele-ε4 of the apolipoprotein E4 gene (APOE-ε4). By themselves, neither HSV1 nor the APOE-ɛ4 allele were found as risk factors for the development of AD but their combination increased the risk of AD development by 12 times and made up 60% in patients with AD. The phenomena involved in the pathophysiology of AD are neurodegenerative changes that occur as a result of fibrillation and deposition of amyloid-β-peptide (Aβ) and neurofibrillary tangles – accumulations of aggregated phosphorylated tau-proteins (P-tau), leading to brain atrophy due to neuronal death. Traditionally, Aβ has been characterized as a catabolic by-product. However, it has recently been shown that Aβ-peptide has antiviral activity and protective effects against HSV infections in the brain. А 16-year study in Thailand with more than 33,000 patients showed that long-term use of antiherpetic drugs reduces the risk of dementia, including AD patients infected with HSV1. Patients with HSV1 infection who received antiherpetic drugs showed a lower risk of all types of dementia compared with the group without these drugs. Their positive effect on stopping the accumulation of amyloid beta and tau protein in the body has been confirmed. In this regard, it is assumed that vaccination against HSV1 may be useful not only for treatment, but also for the prevention of AD.