bay-57-1293 and Herpes-Simplex

Herpes simplex virus (HSV) types 1 and 2 can cause infections with clinical manifestations ranging from benign and generally self-limiting blisters or sores as seen in labial and genital herpes through to severe and in rare cases even life-threatening infections. At present, approved treatments for herpes simplex virus are almost all nucleoside analogs. Novel antiviral approaches include therapeutic vaccines, with the most advanced having successfully completed Phase 2 clinical development. Moreover, several small molecules approaches are being developed for the treatment of genital or labial HSV infections. Of particular interest are two novel compounds (amenamevir and pritelivir) belonging to the new class of helicase-primase inhibitors with promising Phase 2 data.

Topics: Acyclovir; Antiviral Agents; Clinical Trials, Phase II as Topic; DNA Helicases; DNA Primase; Drug Resistance, Viral; Herpes Genitalis; Herpes Simplex; Herpes Simplex Virus Vaccines; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Oxadiazoles; Pyridines; Sulfonamides; Thiazoles; Viral Proteins

The seminal discovery of acyclovir 40 years ago heralded the modern era of truly selective antiviral therapies and this drug remains the therapy of choice for herpes simplex virus infections. Yet by modern standards, its antiviral activity is modest and new drugs against novel molecular targets such as the helicase-primase have the potential to improve clinical outcome, particularly in high-risk patients. A brief synopsis of current therapies for these infections and clinical need is provided to help provide an initial perspective. The function of the helicase-primase complex is then summarized and the development of new inhibitors of the helicase-primase complex, such as pritelivir and amenamevir, is discussed. We review their mechanism of action, propensity for drug resistance, and pharmacokinetic characteristics and discuss their potential to advance current therapeutic options. Strategies that include combinations of these inhibitors with acyclovir are also considered, as they will likely maximize clinical efficacy.

Topics: Acyclovir; Animals; Antiviral Agents; DNA Helicases; DNA Primase; Drug Design; Drug Resistance, Viral; Herpes Simplex; Humans; Molecular Targeted Therapy; Oxadiazoles; Pyridines; Sulfonamides; Thiazoles; Viral Proteins

Helicase-primase inhibitors (HPIs) are the first new family of potent herpes virus (herpes simplex and varicella-zoster virus) inhibitors to go beyond the preliminary stages of investigation since the emergence of the original nucleoside analog inhibitors. To consider the clinical future of HPIs, this review puts the exciting new findings with two HPIs, amenamevir and pritelivir, into the historical context of antiviral development for the prevention and treatment of herpes simplex virus over the last century and, on this basis, the authors speculate on the potential evolution of these and other non-nucleoside inhibitors in the future.

Topics: Antiviral Agents; DNA Helicases; DNA Primase; DNA Replication; Herpes Simplex; Humans; Oxadiazoles; Pyridines; Simplexvirus; Sulfonamides; Thiazoles; Viral Proteins

The majority of the population is infected by several herpesviruses. Once these infections are established the viruses persist for life. Therefore, current therapy may at best reduce symptoms but does not cure the infection. Moreover, the only classes of compounds licensed for systemic treatment of disease are nucleoside, nucleotide and pyrophosphate analogues; all of these ultimately target the herpesvirus DNA polymerase. A vaccine against varicella zoster virus (VZV) is available, but so far no effective vaccines against other human herpesviruses have been launched. At the same time, rising resistance to current medication, especially in the immunocompromised patient population, is a concern. For these reasons, there is an urgent need for new treatment options. Recently, some promising new drugs have been discovered; one of these compounds, developed at Bayer HealthCare under the name BAY 57-1293, is a potent HSV helicase primase inhibitor.

Topics: Antiviral Agents; DNA Helicases; DNA Primase; Enzyme Inhibitors; Herpes Simplex; Humans; Models, Molecular; Pyridines; Simplexvirus; Sulfonamides; Thiazoles; Viral Proteins

We present two allogeneic hematopoietic cell transplantation recipients (HCTr) treated with pritelivir for acyclovir-resistant/refractory (r/r) HSV infection based on the expanded access program of the pritelivir manufacturer. Outpatient treatment with pritelivir was administered, with partial response by week 1 of treatment and complete response by week 4 of treatment in both patients. No adverse events were noted. Pritelivir appears to be an effective and safe option for the management of acyclovir-r/r HSV infections in highly immunocompromised patients in an outpatient setting.

Topics: Acyclovir; Antiviral Agents; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Salvage Therapy; Transplant Recipients

Topics: Acyclovir; Antiviral Agents; Drug Resistance, Viral; Hematopoietic Stem Cell Transplantation; Herpes Simplex; Humans; Salvage Therapy; Transplant Recipients

When the nucleoside analogue acyclovir was introduced in the early 1980s, it presented a game-changing treatment modality for herpes simplex virus infections. Since then, work has been ongoing to improve the weaknesses that have now been identified: a narrow time window for therapeutic success, resistance in immunocompromised patients, little influence on frequency of recurrences, relatively fast elimination, and poor bioavailability. The present Drug Annotation focuses on the helicase-primase inhibitor pritelivir currently in development for the treatment of acyclovir-resistant HSV infections and describes how a change of the molecular target (from viral DNA polymerase to the HSV helicase-primase complex) afforded improvement of the shortcomings of nucleoside analogs. Details are presented for the discovery process leading to the final drug candidate, the pivotal preclinical studies on mechanism of action and efficacy, and on how ongoing clinical research has been able to translate preclinical promises into clinical use.

Topics: Acyclovir; Antiviral Agents; DNA Primase; Drug Resistance, Viral; Herpes Simplex; Humans; Nucleosides; Pyridines

Recurrence of mucocutaneous herpes simplex virus (HSV) infections is common in immunosuppressed patients. Thymidine kinase mutations conferring resistance to the antiviral agent aciclovir have been observed in such patients. Recommended second-line therapeutic agents against HSV are associated with significant side effects contributing to disease burden. We present a case of aciclovir-resistant herpes simplex virus 2 (HSV-2) in an immunosuppressed (HIV negative) allogenic peripheral blood stem cell transplant (SCT) recipient which was refractory to second-line therapy. Compassionate acquisition of the novel oral helicase-primase inhibitor pritelivir provided both symptomatic and virological control for the duration of its use. We believe this to be the first clinical use of this therapeutic agent in the United Kingdom.

Topics: Acyclovir; Aged; Antiviral Agents; Drug Resistance, Viral; Female; Herpes Simplex; Herpesvirus 2, Human; Humans; Pyridines; Sulfonamides; Thiazoles

Herpes simplex virus (HSV) infections can cause considerable morbidity. Currently, nucleoside analogues such as acyclovir are widely used for treatment. However, HSV infections resistant to these drugs are a clinical problem among immunocompromised patients. To provide more efficient therapy and to counteract resistance, a different class of antiviral compounds has been developed. Pritelivir, a helicase primase inhibitor, represents a promising candidate for improved therapy. Here, we established an HSV-1 infection model on microneedle-pretreated human skin ex vivo. We identified HSV-1-specific histological changes (e.g., cytopathic effects, multinucleated giant cells), down-regulation of nectin-1, nuclear translocation of NF-κB (p65), interferon regulatory factor 3 (IRF3), and signaling of the IFN-inducible protein MxA. Accordingly, this model was used to test the potency of pritelivir compared with the standard drug acyclovir. We discovered that both drugs had a comparable efficacy for inhibiting HSV-1 replication, suggesting that pritelivir could be an alternative therapeutic agent for patients infected with acyclovir-resistant strains. To our knowledge, we present a previously unreported ex vivo HSV-1 infection model with abdominal human skin to test antiviral drugs, thus bridging the gap between in vitro and in vivo drug screening and providing a valuable preclinical platform for HSV research.

Topics: Acyclovir; Adult; Aged; Antiviral Agents; Biopsy, Needle; Case-Control Studies; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Immunohistochemistry; In Vitro Techniques; Male; Middle Aged; Models, Biological; Pyridines; Reference Values; Statistics, Nonparametric; Sulfonamides; Thiazoles; Virus Replication; Young Adult

Herpes simplex virus (HSV) infections can cause considerable morbidity. Transmission of HSV-2 has become a major health concern, since it has been shown to promote transmission of other sexually transmitted diseases. Pritelivir (AIC316, BAY 57-1293) belongs to a new class of HSV antiviral compounds, the helicase-primase inhibitors, which have a mode of action that is distinct from that of antiviral nucleoside analogues currently in clinical use. Analysis of pharmacokinetic-pharmacodynamic parameters is a useful tool for the selection of appropriate doses in clinical trials, especially for compounds belonging to new classes for which no or only limited data on therapeutic profiles are available. For this purpose, the effective dose of pritelivir was determined in a comprehensive mouse model of HSV infection. Corresponding plasma concentrations were measured, and exposures were compared with efficacious concentrations derived from cell cultures. The administration of pritelivir at 10 mg/kg of body weight once daily for 4 days completely suppressed any signs of HSV infection in the animals. Associated plasma concentrations adjusted for protein binding stayed above the cell culture 90% effective concentration (EC90) for HSV-1 for almost the entire dosing interval. Interestingly, by increasing the dose 6-fold and prolonging the treatment duration to 8 days, it was possible to treat mice infected with an approximately 30-fold pritelivir-resistant but fully pathogenic HSV-1 virus. Corresponding plasma concentrations exceeded the EC90 of this mutant for <8 h, indicating that even suboptimal exposure to pritelivir is sufficient to achieve antiviral efficacy, possibly augmented by other factors such as the immune system.

Topics: Animals; Antiviral Agents; DNA Primase; DnaB Helicases; Dose-Response Relationship, Drug; Drug Resistance, Viral; Female; Herpes Simplex; Herpesvirus 1, Human; Male; Mice; Mice, Inbred BALB C; Pyridines; Skin Diseases, Viral; Sulfonamides; Thiazoles; Viral Plaque Assay; Virus Replication

Herpes simplex virus type 1 (HSV1) infection of cultured cells causes the formation of β-amyloid (Aβ) and abnormal tau (P-tau). These molecules comprise the main components of the abnormal protein deposits, amyloid plaques and neurofibrillary tangles, respectively, in Alzheimer's disease (AD) brains, and they have been implicated in disease development. The formation of P-tau, but not of Aβ, depends on viral DNA replication, but nonetheless, three antiviral agents that inhibit HSV1 DNA replication, including acyclovir (ACV), were found to reduce greatly the level of Aβ as well as P-tau, the former probably through prevention of viral spread. Previous studies showed that HSV1 DNA is present and is active in the brain of many elderly people, including AD patients, and that in combination with the type 4 allele of the apolipoprotein E gene, it is likely to play a role in the disease, perhaps via Aβ and P-tau production. With the aim of finding the most suitable antiviral for inhibiting Aβ and P-tau formation as well as HSV1 DNA replication, for future use in a clinical trial for treating AD, we compared the efficacy of ACV with that of another antiviral, BAY 57-1293, which acts by a different mechanism from ACV. We found that BAY 57-1293 is more efficient than ACV not only in inhibiting HSV1 replication, confirming previous studies, but also in decreasing Aβ and P-tau formation. Also, the cell clusters that are formed during infection are reduced in size much more efficiently by BAY 57-1293 than by ACV. These data suggest that BAY 57-1293 would be a more effective agent than ACV for treating AD.

Topics: Acyclovir; Alzheimer Disease; Amyloid beta-Peptides; Antiviral Agents; DNA Helicases; DNA Primase; Down-Regulation; Enzyme Inhibitors; Herpes Simplex; Herpesvirus 1, Human; Humans; Pyridines; Sulfonamides; tau Proteins; Thiazoles; Viral Proteins; Virus Replication

Herpes simplex virus (HSV) helicase-primase (HP) is the target for a novel class of antiviral compounds, the helicase-primase inhibitors (HPIs), e.g. BAY 57-1293. Although mutations in herpesviruses conferring resistance to nucleoside analogues are commonly associated with attenuation in vivo, to date, this is not necessarily true for HPIs. HPI-resistant HSV mutants selected in tissue culture are reported to be equally pathogenic compared to parental virus in animal models. Here we demonstrate that a slow-growing HSV-1 mutant, with the BAY 57-1293-resistance mutation Gly352Arg in UL5 helicase, is clearly less virulent than its wild-type parent in a murine zosteriform infection model. This contrasts with published results obtained for a mutant containing a different HPI-resistance substitution (Gly352Val) at the same location, since this mutant was reported to be fully pathogenic. We believe our report to be the first to describe an HPI-resistant HSV-1 mutant, that is markedly less virulent in vivo and slowly growing in tissue culture compared to the parental strain. Another BAY 57-1293-resistant UL5 mutant (Lys356Gln), which showed faster growth characteristics in cell culture, however, was at least equally virulent compared to the parent strain.

Topics: Animals; Antiviral Agents; Chlorocebus aethiops; DNA Helicases; DNA Primase; Drug Resistance, Viral; Enzyme Inhibitors; Herpes Simplex; Herpesvirus 1, Human; Humans; Mice; Mice, Inbred BALB C; Mutation; Pyridines; Sulfonamides; Thiazoles; Vero Cells; Viral Proteins; Virulence

BAY 57-1293 represents a new class of potent inhibitors of herpes simplex virus (HSV) that target the virus helicase primase complex. The present study was conducted using the zosteriform infection model in BALB/c mice. The helicase primase inhibitor, BAY 57-1293 was shown to be highly efficacious in this model. The beneficial effects of therapy were obtained rapidly (within 2 days) although the onset of treatment was delayed for 1 day after virus inoculation. The compound given orally, or intraperitoneally once per day at a dose of 15 mg/kg for 4 successive days was equally effective or superior to a much higher dose of famciclovir (1mg/ml, i.e. approximately 140-200mg/kg/day) given in the drinking water for 7 consecutive days, which, in our hands, is the most effective method for administering famciclovir to mice. In contrast to the vehicle-treated infected mice, all mice that received antiviral therapy looked normal and active with no mortality, no detectable loss of weight and no marked change in ear thickness. BAY 57-1293 and famciclovir reduced the virus titers in the skin to below the level of detection by days 3 and 7 post infection, respectively. In both BAY 57-1293 and famciclovir-treated mice, infectious virus titers in the ear pinna and brainstem remained below the level of detection. Consistent with these findings, BAY 57-1293 also showed a potent antiviral effect in an experiment involving a small number of severely immunocompromised athymic-nude BALB/c mice.

Topics: 2-Aminopurine; Administration, Oral; Animals; Antiviral Agents; Brain Stem; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Ear; Famciclovir; Herpes Simplex; Herpesvirus 1, Human; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Mice, Nude; Pyridines; Skin; Sulfonamides; Thiazoles

Two mutants (BAYr1 and BAYr2) that are 100-fold and >3000-fold resistant, respectively, to the helicase-primase inhibitor (HPI) BAY 57-1293 were derived from a plaque-pure parental strain, HSV-1 SC16 cl-2. BAYr1 has two substitutions in the HSV-1 helicase (UL5) protein (A4 to V; K356 to Q) and BAYr2 has one (G352 to R). It was shown reproducibly that BAYr1 grows to higher titres in tissue culture while BAYr2 grows more slowly than wild-type. Marker transfer experiments confirmed that K356Q and G352R are the drug-resistance mutations and that they are directly associated with differences in virus growth in tissue culture. When BAYr1 was tested in a murine infection model, this virus was shown to be fully pathogenic. We present evidence that single mutations close to a predicted functional domain of an essential HSV-1 replication enzyme (helicase) are associated with drug resistance and virus growth characteristics.

Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Antiviral Agents; Chlorocebus aethiops; DNA Helicases; DNA Primase; Drug Resistance, Viral; Enzyme Inhibitors; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Pyridines; Sulfonamides; Thiazoles; Vero Cells; Viral Proteins; Virus Replication

BAY 57-1293 is a helicase-primase inhibitor (HPI) from a new class of antivirals that are highly efficacious in herpes simplex virus (HSV)-1 animal infection models. Resistant mutants with point mutations in the helicase (UL5) were reported to be present in laboratory isolates at a low frequency of approximately 10(-6). In contrast, we have shown elsewhere that some laboratory isolates contain resistant variants at higher frequency (10(-4)). Therefore, we screened 10 recent clinical isolates of HSV-1 for BAY 57-1293-resistant virions.. Clinical isolates were screened by a plaque reduction assay in Vero cells to determine the frequency of occurrence of BAY 57-1293-resistant variants. The helicase gene for the resistant variants was sequenced.. One isolate contained highly resistant variants at 10(-4) and another at 10(-5). Both variants contained a previously reported BAY 57-1293 resistance mutation (K356N) in UL5 and were >5000-fold resistant.. Occurrence of HPI-resistant viruses at high frequency in a clinical isolate is intriguing. Two alternative hypotheses are proposed to explain this phenomenon. It is also surprising that two unrelated clinical isolates contain an identical HPI resistance mutation. These results have important implications for HPI drug-resistance monitoring during subsequent clinical trials.

Topics: Adult; Amino Acid Sequence; Animals; Chlorocebus aethiops; DNA Helicases; Drug Resistance, Viral; Enzyme Inhibitors; Female; Genes, Viral; Herpes Simplex; Herpesvirus 1, Human; Humans; Male; Molecular Sequence Data; Polymorphism, Genetic; Pyridines; Sulfonamides; Thiazoles; Vero Cells; Viral Plaque Assay

Topics: Animals; Anti-HIV Agents; Antiviral Agents; Cytomegalovirus Infections; Drug Evaluation, Preclinical; Hepatitis B; Herpes Simplex; HIV Infections; Humans; Mice; Naphthalenesulfonates; Pyridines; Pyrimidines; Sulfonamides; Thiazoles; Virus Diseases

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

Topics: Acyclovir; Animals; Antiviral Agents; DNA Helicases; DNA Primase; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Female; Guinea Pigs; Herpes Simplex; Humans; Infant, Newborn; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Pregnancy; Pyridines; Safety; Sulfonamides; Thiazoles; Viral Proteins

BAY 57-1293 belongs to a new class of antiviral compounds and inhibits replication of herpes simplex virus (HSV) type 1 and type 2 in the nanomolar range in vitro by abrogating the enzymatic activity of the viral primase-helicase complex. In various rodent models of HSV infection the antiviral activity of BAY 57-1293 in vivo was found to be superior compared to all compounds currently used to treat HSV infections. The compound shows profound antiviral activity in murine and rat lethal challenge models of disseminated herpes, in a murine zosteriform spread model of cutaneous disease, and in a murine ocular herpes model. It is active in parenteral, oral, and topical formulations. BAY 57-1293 continued to demonstrate efficacy when the onset of treatment was initiated after symptoms of herpetic disease were already apparent.

Topics: Animals; Antibodies, Viral; Antiviral Agents; Blotting, Southern; DNA Helicases; DNA Primase; Drug Resistance, Microbial; Eye; Female; Herpes Simplex; Mice; Mice, Inbred BALB C; Mucous Membrane; Pyridines; Rats; Rats, Inbred Lew; Simplexvirus; Skin; Sulfonamides; Thiazoles