RESUMO
Helicase-primase is an interesting target for the therapy of herpes simplex virus (HSV) infections. Since amenamevir is already approved for varicella-zoster virus (VZV) and HSV in Japan and pritelivir has received breakthrough therapy status for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in me-too approaches. Here, we describe the attempt to improve nervous tissue penetration in Phaeno Therapeutics drug candidate HN0037 to target the latent reservoir of HSV by installing less polar moieties, mainly a difluorophenyl instead of a pyridyl group, and replacing the primary sulfonamide with a methyl sulfoximine moiety. However, all obtained stereoisomers exhibited a weaker inhibitory activity on HSV-1 and HSV-2.
Assuntos
Antivirais , DNA Primase , Sulfonamidas , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , DNA Primase/antagonistas & inibidores , DNA Primase/metabolismo , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , DNA Helicases/antagonistas & inibidores , DNA Helicases/metabolismo , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Estrutura Molecular , Testes de Sensibilidade Microbiana , Relação Dose-Resposta a Droga , Iminas/química , Iminas/farmacologia , Iminas/síntese químicaRESUMO
Herpes is a contagious life-long infection with persistently high incidence and prevalence, causing significant disease worldwide. Current therapies have efficacy against active HSV infections but no impact on the latent viral reservoir in neurons. Thus, despite treatment, disease recurs from latency and the infectious potential remains unaffected within patients. Here, efficacy of the helicase-primase inhibitor (HPI) IM-250 against chronic neuronal HSV infections utilizing two classic herpes in vivo latency/reactivation animal models (intravaginal guinea pig HSV-2 infection model and ocular mouse HSV-1 infection model) is presented. Intermittent therapy of infected animals with 4-7 cycles of IM-250 during latency silences subsequent recurrences analyzed up to 6 months. In contrast to common experience, our studies show that the latent reservoir is indeed accessible to antiviral therapy altering the latent viral reservoir such that reactivation frequency can be reduced significantly by prior IM-250 treatment. We provide evidence that antiviral treatment during HSV latency can reduce future reactivation from the latent reservoir, supporting a conceptual shift in the antiviral field, and reframing what is achievable with respect to therapy of latent neuronal HSV infections.
Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Animais , Camundongos , Cobaias , DNA Primase , Latência Viral/fisiologia , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/fisiologia , Modelos Animais de Doenças , Antivirais/farmacologia , Antivirais/uso terapêuticoRESUMO
Helicase-primase is an interesting target for small-molecule therapy of herpes simplex virus (HSV) infections. With amenamevir already approved for varicella-zoster virus and with pritelivir's granted breakthrough therapy designation for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest for me-too approaches. We describe the opportunities and limitations of the helicase-primase inhibitor patent portfolio from Phaeno Therapeutics and propose the structure of their drug candidate HN0037, which has been in-licensed from Medshine Discovery.
Assuntos
DNA Primase , Herpes Simples , Antivirais/uso terapêutico , DNA Helicases , Herpes Simples/tratamento farmacológico , Humanos , Patentes como Assunto , Proteínas Virais/uso terapêuticoRESUMO
Herpes simplex virus 1 (HSV-1) is a frequently unrecognized, yet deadly cause of acute liver failure (ALF). We, therefore, analysed three cases of fatal HSV-1-induced ALF. All patients shared clinical (extremely elevated transaminases, LDH and AST/LDH ratio < 1) and virological characteristics (ratio of viral load in plasma versus throat swabs: 60-700-fold, lack of anti-HSV-1-IgG antibodies or low IgG-avidity during primary infection), which may help to identify patients at risk. Additionally, in vitro chemosusceptibility assays revealed high efficacy of the helicase-primase inhibitors (HPI), pritelivir and drug-candidate IM-250 compared to acyclovir (ACV) using HSV-1-isolates from two patients; hence, ACV/HPI-combinations might offer new therapeutic options for HSV-induced ALF.
Assuntos
Herpesvirus Humano 1 , Falência Hepática Aguda , Aciclovir/farmacologia , Aciclovir/uso terapêutico , Antivirais/efeitos adversos , DNA Helicases , DNA Primase , Humanos , Imunoglobulina G , Falência Hepática Aguda/induzido quimicamente , Piridinas/efeitos adversosRESUMO
Although the seroprevalence of Herpes simplex virus type 1 (HSV-1) currently amounts to â¼ 67% worldwide, the annual incidence of a severe disease progression, particularly herpes encephalitis, is approximately 2-4 cases per 1,000,000 infections. Nucleoside analogues, such as acyclovir (ACV), valacyclovir (VACV) or famciclovir, are still the therapeutic treatment of choice for HSV infections. However, nucleoside drugs have limited efficacy against severe HSV disease and for treatment of nucleoside-resistant viral strains, alternative therapies such as helicase-primase inhibitors (HPIs) which are highly potent by inhibiting viral replication are under development. In preclinical studies we analyzed the antiviral efficacy of drug candidates of a novel compound class of HPIs for the treatment of HSV to identify the most active eutomer structure in an intranasal infection mouse lethal challenge model. HSV-1 infected BALB/c mice treated with vehicle control developed fatal disease according to humane endpoints after 5-7 days. In contrast, the animals dosed orally once daily with the HPI compounds at 10 or 4 mg/kg/day showed a significantly increased survival (70% and 100% for 10 mg/kg/day; 90% and 100% for 4 mg/kg/day, respectively) compared to the vehicle treatment (0-10%), when therapy was initiated 6 h post HSV-1 inoculation. We observed a significantly improved outcome in clinical parameters and survival over 21 days in the group receiving novel HPI candidates using even the lowest dose of 4 mg/kg/day. With VACV treatment of 75 mg/kg daily survival was also significantly increased (80%-90% for 75 mg/kg/day) but to lesser extent. Initial IM-250 therapy at 10 mg/kg/day could be delayed up to 72 h resulting in significantly increased survival compared to the vehicle control. Furthermore, we detected significantly fewer viral genome copies in the lungs and brains of HPI treated animals compared to vehicle (440-fold reduction for 4 mg/kg/day IM-250 in the brain) or VACV controls by quantitative PCR. In conclusion the preclinical studies of the novel HPI compounds showed superior efficacy in comparison to the current standard HSV treatment represented by VACV with respect to the survival according humane endpoints, the clinical score and virus load in lungs and brains. Thus, candidates of this new drug class are promising antivirals of HSV infections and further translation into clinical trials is warranted.
Assuntos
Antivirais/farmacologia , DNA Helicases/antagonistas & inibidores , DNA Primase/antagonistas & inibidores , Herpes Simples/virologia , Herpesvirus Humano 1/efeitos dos fármacos , Aciclovir/farmacologia , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Herpes Simples/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Taxa de Sobrevida , Valaciclovir/farmacologia , Células Vero , Carga Viral/efeitos dos fármacosRESUMO
More than 50% of the world population is chronically infected with herpesviruses. Herpes simplex virus (HSV) infections are the cause of herpes labialis (cold sores), genital herpes, and sight-impairing keratitis. Less frequently, life-threatening disseminated disease (encephalitis and generalized viremia) can also occur, mainly in immunocompromised patients and newborns. After primary infection, HSV persists for life in a latent state in trigeminal or sacral ganglia and, triggered by diverse stimuli, disease recurs in more than 30% of patients up to several times a year. Current therapy with nucleoside analogs targeting the viral polymerase is somewhat effective but limited by poor exposure in the nervous system, and latent infections are not affected by therapy. Here, we report on an inhibitor of HSV helicase-primase with potent in vitro anti-herpes activity, a different mechanism of action, a low frequency of HSV resistance, and a favorable pharmacokinetic and safety profile. Improved target tissue exposure results in superior efficacy in preventing and treating HSV infection and disease in animal models as compared to standard of care. Therapy of primary HSV infections with drug candidate IM-250 {(S)-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5-(S-methylsulfon-imidoyl)thiazol-2-yl)acetamide} not only reduces the duration of disease symptoms or time to healing but also prevents recurrent disease in guinea pigs. Treatment of recurrent infections reduces the frequency of recurrences and viral shedding, and, unlike nucleosidic drugs, IM-250 remains effective for a time after cessation of treatment. Hence, IM-250 has advantages over standard-of-care therapies and represents a promising therapeutic for chronic HSV infection, including nucleoside-resistant HSV.
Assuntos
Antivirais , Herpes Simples , Latência Viral/efeitos dos fármacos , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , DNA Primase , Cobaias , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 2 , Humanos , Sistema NervosoRESUMO
The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with small molecule therapeutics. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We recently described the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an additional amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallographic analysis of compound 1g bound in the sterol binding site of the ligand binding domain of RORγt was largely consistent with an earlier structure, guiding further insight into the molecular mechanism for RORγt inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclinical evaluation.
Assuntos
Amidas/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Bibliotecas de Moléculas Pequenas/química , Tiazóis/química , Doenças Autoimunes/tratamento farmacológico , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Interleucina-17/química , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacologiaRESUMO
Starting from previously identified thiazole-2-carboxamides exemplified by compound 1/6, two new series of RORγt inverse agonists with significantly improved aqueous solubility, ADME parameters and oral PK properties were discovered. These scaffolds were identified from a bioisosteric amide replacement approach. Amongst the variety of heterocycles explored, a 1,3,4-oxadiazole led to compounds with the best overall profile for SAR development and in vivo exploration. In an ex vivo mouse PD model, concentration dependent efficacy was demonstrated and compounds 3/5 and 6/3 were profiled in a 5-day rat tolerability study.
Assuntos
Amidas/farmacologia , Descoberta de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Oxidiazóis/farmacologia , Tiazóis/farmacologia , Administração Oral , Amidas/administração & dosagem , Amidas/química , Animais , Relação Dose-Resposta a Droga , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxidiazóis/administração & dosagem , Oxidiazóis/química , Ratos , Relação Estrutura-Atividade , Tiazóis/administração & dosagem , Tiazóis/químicaRESUMO
Following the impressive success of checkpoint inhibitors in the treatment of cancer, combinations of IDO1 inhibitors with PD-1/PD-L1 antibodies are in clinical development aiming to increase response rates. Using the hydroxyamidine pharmacophore of the IDO1 inhibitor INCB14943 as a starting point for the design of new inhibitors, the potential shortcomings of extensive hydroxyamidine glucuronidation in humans was addressed. Compounds were optimized using a stability assay with recombinant UGT1A9 enzyme together with the measurement of glucuronide formation in human hepatocytes. Optimized analog 24 showed cellular and biochemical IDO1 IC50 values in the low nanomolar range, a suitable in vitro ADME/PK profile, and efficacy in an animal model of cancer. In a humanized liver mouse model the lead compound exhibited significantly reduced glucuronidation compared to epacadostat (2).
RESUMO
The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORγt inhibition with this series.
Assuntos
Receptores do Ácido Retinoico/agonistas , Tiazóis/farmacologia , Animais , Cristalografia por Raios X , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Fungal infections are a serious health problem in clinics, especially in the immune-compromised patient. Disease ranges from widespread superficial infections like vulvovaginal infections to life-threatening systemic candidiasis. Especially for systemic mycoses, only a limited arsenal of antifungals is available. The most commonly used classes of antifungal compounds used include azoles, polyenes, and echinocandins. Due to emerging resistance to standard therapy, significant side effects, and high costs for several antifungals, there is a medical need for new antifungals in the clinic and general practice. In order to expand the arsenal of compounds with antifungal activities, we screened a compound library including more than 35,000 individual compounds derived from organic synthesis as well as combinatorial compound collections representing mixtures of compounds for antimycotic activity. In total, more than 100,000 compounds were screened using a new type of activity-selectivity assay, analyzing both the antifungal activity and the compatibility with human cells at the same time. One promising hit, an (S)-2-aminoalkyl benzimidazole derivative, was developed among a series of lead compounds showing potent antifungal activity. (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl) benzimidazole showed the highest antifungal activity and the best compatibility with human cells in several cell culture models and against a number of clinical isolates of several species of pathogenic Candida yeasts. Transcriptional profiling indicates that the newly discovered compound is a potential inhibitor of the ergosterol pathway, in contrast to other benzimidazole derivatives, which target microtubules.
Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Animais , Antifúngicos/química , Antifúngicos/toxicidade , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Células CHO , Candida/genética , Candida/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Linhagem Celular , Cricetinae , Farmacorresistência Fúngica , Ergosterol/antagonistas & inibidores , Genoma Fúngico , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , Análise de Sequência com Séries de Oligonucleotídeos , Relação Estrutura-Atividade , Transcrição GênicaRESUMO
Novel nontoxic (S)-2-aminoalkylbenzimidazole derivatives were found to be effective against Candida spp. at low micromolar concentrations using high-throughput screening with infected HeLa cells. A collection of analogues defined the chemical groups relevant for activity. The most active compound was characterized by transcriptional analysis of the response of C. albicans Sc5314. (S)-2-(1-Aminoisobutyl)-1-(3-chlorobenzyl)benzimidazole had a strong impact on membrane biosynthesis. Testing different clinically relevant pathogenic fungi showed the selectivity of the antimycotic activity against Candida species.
Assuntos
Antimitóticos/síntese química , Benzimidazóis/síntese química , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Antimitóticos/farmacologia , Antimitóticos/toxicidade , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Candida/efeitos dos fármacos , Candida/genética , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Ensaios de Triagem em Larga Escala , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Imidazóis/toxicidade , Testes de Sensibilidade Microbiana , Micologia/métodos , Estereoisomerismo , Relação Estrutura-Atividade , Transcrição Gênica/efeitos dos fármacosRESUMO
OBJECTIVES: To investigate the mechanism of action of the helicase-primase inhibitors (HPIs) BAY 57-1293 and BILS 22 BS by selection and characterization of drug-resistant herpes simplex virus (HSV)-1 mutants. METHODS: HSV-1 mutants were selected using BAY 57-1293 in Vero cells. Resistance mutations identified in the UL5 helicase or UL52 primase genes were validated by marker transfer. Cross-resistance to the structurally distinct BILS 22 BS was measured by ID(50) determinations. RESULTS: (i) A single mutation (UL52: A899T) confers 43-fold resistance to BAY 57-1293, but does not confer any resistance to BILS 22 BS. (ii) A double mutant (UL52: A899T and UL5: K356T) is 2500-fold resistant to BAY 57-1293, which is more than 17 times the sum of fold-resistance due to the individual mutations, UL52: A899T (43-fold) and UL5: K356T (100-fold). (iii) Virus containing the single helicase mutation and the double mutant with mutations in both helicase and primase showed equal resistance to BILS 22 BS (70-fold). CONCLUSIONS: By measuring the relative inhibitory concentrations required to overcome particular mutations in the helicase and primase proteins, evidence was obtained that BAY 57-1293 interacts with both components of the helicase-primase complex to achieve maximum potency, whereas for BILS 22BS, this may not be the case. Furthermore, our observations suggest that BAY 57-1293 interacts simultaneously with UL5 and UL52. Overall, the results suggest that these two potent HPIs interact differently with the helicase-primase complex.
Assuntos
Antivirais/farmacologia , DNA Helicases/antagonistas & inibidores , DNA Helicases/genética , DNA Primase/antagonistas & inibidores , DNA Primase/genética , Farmacorresistência Viral/genética , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/genética , Piridinas/farmacologia , Tiazóis/farmacologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética , Relação Dose-Resposta a Droga , Herpesvirus Humano 1/enzimologia , SulfonamidasRESUMO
PURPOSE: The aim of this study was to evaluate the effect of BAY 57-1293, a helicase-primase inhibitor, on herpes simplex virus type 1 (HSV-1) reactivation in mice and its efficacy on established disease in rabbits. METHODS: BALB/c mice latent for McKrae-strain HSV-1 were reactivated via heat stress, treated with BAY 57-1293, and their corneas were swabbed for virus or the trigeminal ganglia (TG) obtained for quantification of viral DNA. New Zealand white rabbits were infected and treated topically or orally in comparison with trifluridine or valacyclovir. RESULTS: Oral BAY 57-1293 suppressed reactivation in HSV-1-infected mice and reduced the viral load in TG up to four orders of magnitude. In the rabbits, the therapeutic efficacies of topical BAY 57-1293 and trifluridine were similar. Once-daily oral BAY 57-1293 was significantly more effective than valacyclovir and as effective as twice a day topical trifluridine. CONCLUSIONS: BAY 57-1293 may be more effective than valacyclovir, without the cytotoxicity or potential healing retardation seen with trifluridine. Oral BAY 57-1293 may be a substitute for eye drops as an effective treatment for herpetic keratitis and might be useful in treating stromal keratitis and iritis, as well as preventing recurrences of ocular herpes.
Assuntos
DNA Helicases/antagonistas & inibidores , DNA Primase/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Ceratite Herpética/tratamento farmacológico , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Proteínas Virais/antagonistas & inibidores , Animais , DNA Viral/química , Feminino , Transtornos de Estresse por Calor/virologia , Herpesvirus Humano 1 , Camundongos , Camundongos Endogâmicos BALB C , Coelhos , Sulfonamidas , Lágrimas/virologia , Gânglio Trigeminal/virologia , Eliminação de Partículas Virais/efeitos dos fármacosRESUMO
The efficacy of BAY 57-1293, a novel non-nucleosidic inhibitor of herpes simplex virus 1 and 2 (HSV-1 and HSV-2), bovine herpesvirus and pseudorabies virus, was studied in the guinea pig model of genital herpes in comparison with the licensed drug valaciclovir (Valtrex). Early therapy with BAY 57-1293 almost completely suppressed the symptoms of acute HSV-2 infection, and reduced virus shedding and viral load in the sacral dorsal root ganglia by up to three orders of magnitude, resulting in decreased latency and a greatly diminished frequency of subsequent recurrent episodes. In contrast, valaciclovir showed only moderate effects in this set of experiments. When treatment was initiated late during the course of disease after symptoms were apparent, that is, a setting closer to most clinical situations, the efficacy of therapy with BAY 57-1293 was even more pronounced. Compared with valaciclovir, BAY 57-1293 halved the time necessary for complete healing. Moreover, the onset of action was fast, so that only very few animals developed new lesions after treatment commenced. Finally, in a study addressing the treatment of recurrent disease in animals whose primary infection had remained untreated BAY 57-1293 was efficient in suppressing the episodes. In summary, superior potency and efficacy of BAY 57-1293 over standard treatment with valaciclovir was demonstrated in relevant animal models of human genital herpes disease in terms of abrogating an HSV infection, reducing latency and the frequency of subsequent recurrences. Furthermore, BAY 57-1293 shortens the time to healing even if initiation of therapy is delayed.
Assuntos
Antivirais/farmacologia , DNA Helicases/antagonistas & inibidores , DNA Primase/antagonistas & inibidores , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Herpes Genital/tratamento farmacológico , Piridinas/farmacologia , Tiazóis/farmacologia , Animais , Antivirais/uso terapêutico , DNA Viral/genética , Inibidores Enzimáticos/uso terapêutico , Cobaias , Herpesvirus Humano 2/genética , Humanos , Reação em Cadeia da Polimerase , Piridinas/uso terapêutico , Sulfonamidas , Tiazóis/uso terapêuticoRESUMO
The quiet pandemic of herpes simplex virus (HSV) infections has plagued humanity since ancient times, causing mucocutaneous infection such as herpes labialis and herpes genitalis. Disease symptoms often interfere with every-day activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immuno-compromised patient population. After infection the virus persists for life in neurons of the host in a latent form, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently no cure is available. So far, vaccines, ILs, IFNs, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or non-specific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. The recently discovered inhibitors of the HSV helicase-primase are the most potent development candidates today. These antiviral agents act by a novel mechanism of action and display low resistance rates in vitro and superior efficacy in animal models. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease.
Assuntos
Antivirais/uso terapêutico , Drogas em Investigação/uso terapêutico , Herpes Simples/tratamento farmacológico , Tecnologia Farmacêutica/tendências , Antivirais/química , Antivirais/farmacologia , Gerenciamento Clínico , Drogas em Investigação/química , Drogas em Investigação/farmacologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Simplexvirus/efeitos dos fármacos , Tecnologia Farmacêutica/métodosRESUMO
Efficacy and tolerability are the key criteria for a successful medication in the clinic. Therefore, a new test method to obtain selective and active lead molecules has been developed. Recently, this novel screening strategy enabled a breakthrough in drug discovery in the field of herpes viruses. Here the authors report that this assay is a generally applicable screening test, which allows not only for identifying tolerable and potent antimicrobial agents in compound libraries, but also covers all potential in vitro targets of both the pathogen and the host simultaneously. The test system mimics the smallest unit of a natural infection. Host cells are incubated in the presence of the test sample and are infected with microbes, such as viruses, bacteria, or fungi. Analogous to (lethal challenge) animal models, cell survival is determined. This assay maximizes the chances of success of anti-infective drug discovery, is sensitive, robust, time- and cost-efficient, and especially effective in optimizing screening hits to lead structures and development candidates. In addition to the minimal inhibitory concentration or dose, this test system simultaneously provides the selectivity index, a measure of tolerability in vitro. The authors propose the activity selectivity assay format as a new standard in anti-infective drug discovery and clinical development.
Assuntos
Anti-Infecciosos/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Animais , Bactérias/patogenicidade , Bactérias/ultraestrutura , Células CHO , Sobrevivência Celular , Chlorocebus aethiops , Cricetinae , Cricetulus , Células HeLa , Humanos , Microscopia Eletrônica de Varredura , Estrutura Molecular , Células VeroRESUMO
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.
Assuntos
Antivirais/farmacologia , DNA Helicases/antagonistas & inibidores , DNA Primase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herpes Simples/tratamento farmacológico , Piridinas/farmacologia , Simplexvirus/enzimologia , Tiazóis/farmacologia , Antivirais/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Modelos Moleculares , Piridinas/uso terapêutico , Sulfonamidas , Tiazóis/uso terapêutico , Proteínas Virais/antagonistas & inibidoresRESUMO
Herpesviruses have infected the majority of the world's population and the associated diseases have plagued humanity since ancient times. Nine causative human herpesviruses have been identified so far. The first antiviral drug was launched in 1962, and since then several drugs for treating herpesvirus infections, which work via different mechanisms, have been developed. Current treatments abrogate or suppress disease symptoms but are not curative. A vaccine based on the OKA strain of varicella zoster virus is being marketed, but to date no therapeutic or prophylactic herpes vaccinations that can treat or stop spread of other herpes diseases are available. Herpes simplex virus causes mucocutaneous infections such as herpes genitalis (genital herpes) and herpes labialis (cold sores), the potentially sight-impairing herpetic eye disease, and life-threatening herpes encephalitis or disseminated disease. Recently, reports of helicase primase inhibitors, the first non-nucleosidic antiviral compounds, which are superior in pre-clinical profile to current herpes simplex virus medication, have been published. This review summarizes the data on helicase primase inhibitors and compares their pre-clinical profile with the established medical standard.
Assuntos
Antivirais/uso terapêutico , DNA Helicases/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Herpes Simples/tratamento farmacológico , Simplexvirus/enzimologia , Animais , DNA Primase , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Herpes Simples/enzimologia , Humanos , Proteínas ViraisRESUMO
Monorden (1) and the novel resorcylic acid lactones pochonins A (2), B (4), C (6), D (7), and E (8) as well as tetrahydromonorden (5) and pseurotin A (22) were isolated from cultures of the clavicipitaceous hyphomycete Pochonia chlamydosporia var. catenulata strain P 0297. Fermentation of P 0297 in bromide-containing culture media led to a shift in secondary metabolite production and yielded monocillins III (3) and II (9) as major metabolites besides monorden (1) as well as the novel compounds pochonin F (10) and a monocillin II glycoside (11) as minor metabolites. Most of these compounds showed moderate activities in a cellular replication assay against Herpes Simplex Virus 1 (HSV1) and against the parasitic protozoan Eimeria tenella. In contrast to the structurally related zearalenone derivatives none of the metabolites of strain P 0297 were found to be active in a fluorescence polarization assay for determination of modulatory activities on the human estrogenic receptor ERbeta. Beta-zearalenol (17), but not zearalenone (15) and alpha-zearalenol (16), showed antiherpetic effects. We report the production, isolation, and structure elucidation of compounds 1-11 and their biological characterization.