Current challenges in the discovery of treatments against Mayaro fever.

INTRODUCTION: Mayaro fever is an emerging viral disease that manifests as an acute febrile illness. The disease is self-limiting, however joint pain can persist for months leading to chronic arthralgia. There is no specific treatment available, which ultimately leads to socioeconomic losses in populations at risk as well as strains to the public health systems. AREAS COVERED: We reviewed the candidate treatments proposed for Mayaro virus (MAYV) infection and disease, including antiviral compounds targeting viral or host mechanisms, and pathways involved in disease development and pathogenicity. We assessed compound screening technologies and experimental infection models used in these studies and indicated the advantages and limitations of available technologies and intended therapeutic strategies. EXPERT OPINION: Although several compounds have been suggested as candidate treatments against MAYV infection, notably those with antiviral activity, most compounds were assessed only in vitro. Compounds rarely progress toin vivo or preclinical studies, and such difficulty may be associated with limited experimental models. MAYV biology is largely inferred from related alphaviruses and reflected by few studies focusing on target proteins or mechanisms of action for MAYV. Therapeutic strategies targeting pathogenic inflammatory responses have shown potential against MAYV-induced disease in vivo, which might reduce long-term sequelae.

Reactivity and binding mode of disulfiram, its metabolites, and derivatives in SARS-CoV-2 PLpro: insights from computational chemistry studies.

The papain-like protease (PLpro) from SARS-CoV-2 is an important target for the development of antivirals against COVID-19. The safe drug disulfiram (DSF) presents antiviral activity inhibiting PLpro in vitro, and it is under clinical trial studies, indicating to be a promising anti-COVID-19 drug. In this work, we aimed to understand the mechanism of PLpro inhibition by DSF and verify if DSF metabolites and derivatives could be potential inhibitors too. Molecular docking, DFT, and ADMET techniques were applied. The carbamoylation of the active site cysteine residue by DSF metabolite (DETC-MeSO) is kinetically and thermodynamically favorable (ΔG‡ = 3.15 and ΔG = - 12.10 kcal mol-1, respectively). Our results strongly suggest that the sulfoxide metabolites from DSF are promising covalent inhibitors of PLpro and should be tested in in vitro and in vivo assays to confirm their antiviral action.

In Silico Screening of Natural Products Isolated from Mexican Herbal Medicines against COVID-19.

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for all countries. In this sense, research for novel molecules becomes essential to develop treatments against the SARS-CoV-2 virus. In this context, Mexican natural products have proven to be quite useful for drug development; therefore, in the present study, we perform an in silico screening of 100 compounds isolated from the most commonly used Mexican plants, against the SARS-CoV-2 virus. As results, we identify ten compounds that meet leadlikeness criteria (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin). According to the docking analysis, only three compounds target the key proteins of SARS-CoV-2 (quercetin, riolozatrione and cichoriin), but only one appears to be safe (cichoriin). ADME (absorption, distribution, metabolism and excretion) properties and the physiologically based pharmacokinetic (PBPK) model show that cichoriin reaches higher lung levels (100 mg/Kg, IV); therefore, it may be considered in developing therapeutic tools.

Current Antivirals and Novel Botanical Molecules Interfering With Herpes Simplex Virus Infection.

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent within the human population and are characterized by lifelong infections and sporadic recurrences due to latent neuron infection. Upon reactivations, HSVs may manifest either, symptomatically or asymptomatically and be shed onto others through mucosae body fluids. Although, HSVs can produce severe disease in humans, such as life-threatening encephalitis and blindness, the most common symptoms are skin and mucosal lesions in the oro-facial and the genital areas. Nucleoside analogs with antiviral activity can prevent severe HSV infection, yet they are not very effective for treating skin manifestations produced by these viruses, as they only reduce in a few days at most the duration of lesions. Additionally, HSV variants that are resistant to these antivirals may arise, especially in immunosuppressed individuals. Thus, new antivirals that can reduce the severity and duration of these cutaneous manifestations would certainly be welcome. Here, we review currently available anti-herpetic therapies, novel molecules being assessed in clinical trials and new botanical compounds reported in the last 20 years with antiviral activities against HSVs that might represent future treatments against these viruses.

Errores en la oportunidad y dosificación de aciclovir o valaciclovir en el tratamiento del herpes zoster / Erroneous prescriptions of aciclovir and valaciclovir in herpes zoster treatment

Medical prescription errors are frequent in community settings and information exploring its magnitude during antiviral treatment of herpes zoster is scarce. A questionnaire was applied to 31 physicians working in hospital- or community-based settings in Santiago, Chile in order to characterize their dosing and timing preferences for aciclovir or valaciclovir prescriptions. Aciclovir was more often prescribed than valaciclovir (71.9 and 28.1 percent, respectively), but less than a third of prescription (27.3 percent) fulfilled the minimal aciclovir dosing and timing criteria for clinical efficacy (4 gr per day and < 72 hours since rash initiaton). The limited size of the simple prevented exploring factors linked to a misleading prescription. Appropriate knowledge on dosing and timing of aciclovir/valaciclovir therapy for herpes zoster was infrequent in a sample of physicians working in various clinical settings in Chile.

Los errores en la prescripción de medicamentos son frecuentes en escenarios ambulatorios y no hay información disponible sobre el uso de antivirales en el tratamiento del herpes zoster. Para conocer la dosis y oportunidad en la prescripción de aciclovir o valaciclovir se aplicó un cuestionario a 31 médicos que trabajan en hospitales o sitios de atención primaria en Santiago y que declararon haber atendido este tipo de pacientes. El compuesto aciclovir fue más indicado que valaciclovir (71,9 vs 28,1 por ciento) pero menos de un tercio de las prescripciones (27,3 por ciento) cumplieron simultáneamente con una dosis mínima (4 g/día) y ventanas de tiempo apropiadas de aciclovir (hasta 72 horas del rash). El reducido tamaño de la muestra impidió efectuar un análisis de los factores ligados a este fenómeno. El conocimiento apropiado sobre dosis y oportunidad de aciclovir o valaciclovir fue infrecuente en un grupo de médicos que declararon atender pacientes con herpes zoster en Santiago.