Alerta monitoramento do horizonte tecnológico: Tecovirimat para o tratamento da monkeypox / Technological horizon monitoring alert: Tecovirimat for the treatment of monkeypox

A TECNOLOGIA: Descrição da tecnologia: Tecovirimat é um antiviral sintético inibidor da atividade da proteína viral VP37, indicado para o tratamento da infecção por monkeypox. A proteína VP37, codificada por um gene altamente conservado do gênero orthopoxvirus, está presente na superfície do vírus e envolvida no processo de encapsulação e secreção de suas formas extracelulares. O fármaco inibe o último estágio de replicação viral, a partir do bloqueio da interação de VP37 com proteínas celulares do hospedeiro (Rab9 GTPase e TIP47), o que impede a formação de viriões encapsulados competentes, necessários para a disseminação sanguínea, célula a célula e de longo alcance do vírus. A atividade antiviral de tecovirimat é específica para os orthopoxvirus, ou seja, não inibe a ação de outros tipos de DNA ou RNA-vírus e a proliferação celular. Em estudos pré-clínicos com modelos animais, o fármaco demonstrou boa eficácia contra a monkeypox quando administrado no início da infecção, aumentando as taxas de sobrevivência. A segurança e a tolerabilidade do medicamento também foram apontadas em ensaios clínicos com humanos, sendo raros os eventos adversos (náusea e cefaleia). Entretanto, a eficácia de tecovirimat em humanos ainda não foi bem estabelecida. O medicamento pode afetar a imunogenicidade quando administrado concomitantemente com a vacina ACAM2000. INFORMAÇÕES REGULATÓRIAS: Informações sobre registro: No dia 26 de agosto de 2022, a Agência Nacional de Vigilância Sanitária (Anvisa) aprovou a dispensa de registro para importação e uso exclusivo pelo Ministério da Saúde do medicamento tecovirimat no tratamento da monkeypox no Brasil (RDC 747/2022). Essa dispensa é temporária, com validade de seis meses, desde que não seja expressamente revogada pela Anvisa. O medicamento aprovado está disponível na forma de cápsulas duras com concentração de 200 mg, destinadas à administração oral, para o tratamento de doenças causadas pelo orthopoxvirus em adultos, adolescentes e crianças com peso corporal mínimo de 13 kg12. PANORAMA DE DESENVOLVIMENTO: Estratégia de busca: Foi realizada uma busca no ClinicalTrials.gov14 e no Cortellis1 em 30 de agosto de 2022 para a identificação de ensaios clínicos (em qualquer fase em andamento ou finalizados em até cinco anos, registrados no ClinicalTrials.gov) que avaliassem o uso de tecovirimat no tratamento da monkeypox. A busca identificou seis ensaios clínicos, sendo que cinco avaliavam a tecnologia em questão para smallpox; o outro avaliava o uso de tecorivimat para orthopoxvirus, entretanto, foi finalizado em 2010. Portanto, nenhum ensaio clínico atendeu aos critérios de inclusão. CONSIDERAÇÕES FINAIS: A monkeypox é uma doença zoonótica viral causada por um orthopoxvirus, também denominado monkeypox, endêmica das regiões de floresta tropical da África, principalmente na África Ocidental e Central. Devido ao rápido aumento de incidência de casos da doença em países não endêmicos, a partir da transmissão humana, em julho de 2022, a OMS decretou Emergência de Saúde Pública de Importância Internacional. Atualmente, a única tecnologia disponível para o tratamento de monkeypox é o tecovirimat, cuja dispensa de registro foi aprovada pela Anvisa em agosto de 2022. Devido à raridade da doença, a efetividade do medicamento foi avaliada apenas em estudos pré-clínicos conduzidos com animais infectados. Segundo os resultados desses estudos, o medicamento foi capaz de reduzir em cerca de 80% o risco de morte quando o tratamento era iniciado entre o quarto e quinto dia da infecção. Em estudos de segurança com humanos não infectados, o medicamento apontou para adequada segurança e tolerabilidade, sendo os eventos adversos mais comuns náusea e cefaleia. Diante disso, essa tecnologia tem potencial de auxiliar no controle dos casos de monkeypox no Brasil. Para que ocorra a oferta desse medicamento no SUS, é necessária sua análise pela Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde (Conitec), conforme disposto na Lei nº 12.401/2011, que alterou a Lei nº 8.080/1990. Os relatórios de recomendação da Conitec levam em consideração as evidências científicas sobre eficácia, a acurácia, a efetividade e a segurança do medicamento, e, também, a avaliação econômica comparativa dos benefícios e dos custos em relação às tecnologias já incorporadas e o impacto da incorporação da tecnologia no SUS. Ressalta-se a excepcionalidade prevista no art. 29 do Decreto 7.646/2011, que prevê que o Ministro de Estado da Saúde poderá, em caso de relevante interesse público, mediante processo administrativo simplificado, determinar a incorporação ou alteração pelo SUS de tecnologias em saúde. O comando é regulamentado pelos arts. 25-A e 25-B do anexo XVI da Portaria de Consolidação GM/MS nº 1/201716. Conforme o normativo, considera-se caso de relevante interesse público a situação de emergência em saúde pública de importância nacional.

The application of in silico experimental model in the assessment of ciprofloxacin and levofloxacin interaction with main SARS-CoV-2 targets: S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLpro)-preliminary molecular docking analysis.

BACKGROUND: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified at the end of 2019. Despite growing understanding of SARS-CoV-2 in virology as well as many molecular studies, except remdesivir, no specific anti-SARS-CoV-2 drug has been officially approved. METHODS: In the present study molecular docking technique was applied to test binding affinity of ciprofloxacin and levofloxacin-two commercially available fluoroquinolones, to SARS-CoV-2 S-, E- and TMPRSS2 proteins, RNA-dependent RNA polymerase and papain-like protease (PLPRO). Chloroquine and dexamethasone were used as reference positive controls. RESULTS: When analyzing the molecular docking data it was noticed that ciprofloxacin and levofloxacin possess lower binding energy with S protein as compared to the references. In the case of TMPRSS2 protein and PLPRO protease the best docked ligand was levofloxacin and in the case of E proteins and RNA-dependent RNA polymerase the best docked ligands were levofloxacin and dexamethasone. Moreover, a molecular dynamics study also reveals that ciprofloxacin and levofloxacin form a stable complex with E- and TMPRSS2 proteins, RNA polymerase and papain-like protease (PLPRO). CONCLUSIONS: The revealed data indicate that ciprofloxacin and levofloxacin could interact and potentially inhibit crucial SARS-CoV-2 proteins.

α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment.

The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.

Drugs in development for herpes simplex and varicella zoster virus.

The alpha-herpesviruses varicella zoster virus (VZV) and herpes simplex virus (HSV) share common features including lifelong persistence in sensory ganglia and the risk of recurrences. For both HSV and VZV, standard-of-care (SoC) is based on nucleoside analogs (NAs), which require specific activation in infected cells. These existing drugs exhibit substantial limitations, warranting the development of new and more effective drugs.

Risk assessment of recent Egyptian H5N1 influenza viruses.

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are enzootic in poultry populations in different parts of the world, and have caused numerous human infections in recent years, particularly in Egypt. However, no sustained human-to-human transmission of these viruses has yet been reported. We tested nine naturally occurring Egyptian H5N1 viruses (isolated in 2014-2015) in ferrets and found that three of them transmitted via respiratory droplets, causing a fatal infection in one of the exposed animals. All isolates were sensitive to neuraminidase inhibitors. However, these viruses were not transmitted via respiratory droplets in three additional transmission experiments in ferrets. Currently, we do not know if the efficiency of transmission is very low or if subtle differences in experimental parameters contributed to these inconsistent results. Nonetheless, our findings heighten concern regarding the pandemic potential of recent Egyptian H5N1 influenza viruses.

Assessment of Antiviral Properties of Peramivir against H7N9 Avian Influenza Virus in an Experimental Mouse Model.

The H7N9 influenza virus causes a severe form of disease in humans. Neuraminidase inhibitors, including oral oseltamivir and injectable peramivir, are the first choices of antiviral treatment for such cases; however, the clinical efficacy of these drugs is questionable. Animal experimental models are essential for understanding the viral replication kinetics under the selective pressure of antiviral agents. This study demonstrates the antiviral activity of peramivir in a mouse model of H7N9 avian influenza virus infection. The data show that repeated administration of peramivir at 30 mg/kg of body weight successfully eradicated the virus from the respiratory tract and extrapulmonary tissues during the acute response, prevented clinical signs of the disease, including neuropathy, and eventually protected mice against lethal H7N9 influenza virus infection. Early treatment with peramivir was found to be associated with better disease outcomes.

Cell culture-selected substitutions in influenza A(H3N2) neuraminidase affect drug susceptibility assessment.

Assessment of drug susceptibility has become an integral part of influenza virus surveillance. In this study, we describe the drug resistance profile of influenza A(H3N2) virus, A/Mississippi/05/2011, collected from a patient treated with oseltamivir and detected via surveillance. An MDCK cell-grown isolate of this virus exhibited highly reduced inhibition by the neuraminidase (NA) inhibitors (NAIs) oseltamivir (8,005-fold), zanamivir (813-fold), peramivir (116-fold), and laninamivir (257-fold) in the NA inhibition assay. Sequence analysis of its NA gene revealed a known oseltamivir-resistance marker, the glutamic acid-to-valine substitution at position 119 (E119V), and an additional change, threonine to isoleucine at position 148 (T148I). Unlike E119V, T148I was not detected in the clinical sample but acquired during viral propagation in MDCK cells. Using recombinant proteins, T148I by itself was shown to cause only a 6-fold increase in the zanamivir 50% inhibitory concentration (IC50) and had no effect on inhibition by other drugs. The T148I substitution reduced NA activity by 50%, most likely by affecting the positioning of the 150 loop at the NA catalytic site. Using pyrosequencing, changes at T148 were detected in 35 (23%) of 150 MDCK cell-grown A(H3N2) viruses tested, which was lower than the frequency of changes at D151 (85%), an NA residue previously implicated in cell selection. We demonstrate that culturing of the A(H3N2) viruses (n = 11) at a low multiplicity of infection delayed the emergence of the NA variants with changes at position 148 and/or 151, especially when conducted in MDCK-SIAT1 cells. Our findings highlight the current challenges in monitoring susceptibility of influenza A(H3N2) viruses to the NAI class of antiviral drugs.

Oseltamivir use in adolescents and adults: clinical and economic considerations.

Influenza remains an important cause of morbidity and mortality, and incurs substantial economic costs (mainly due to hospitalisation) especially for the elderly aged 65 years or more, and among those with high-risk medical conditions. Influenza vaccination is the most effective control measure for both healthy populations and the chronically ill in whom complications of influenza cluster. Unfortunately, vaccination is less effective in the elderly and immunocompromised persons. Additional benefit may accrue from other health care interventions including antiviral therapy. Oseltamivir, a neuraminidase inhibitor, has become a drug of public health importance since it was included in influenza pandemic management plans. Many systematic reviews and meta-analyses of oseltamivir treatment and prophylaxis trials have been published. We provide a summary of the conclusions and review the various findings of economic analyses. Future randomised controlled trials should focus upon costly outcomes such as hospital admissions and should be conducted in populations at high risk of complications from influenza. Future economic analyses need to address variation in (1) willing-to-pay value, (2) annual attack rate of influenza, and (3) influenza vaccination effectiveness and uptake rates.

Using RNAi in the clinic.

RNA interference (RNAi) is a biological process that controls gene silencing in all living cells. Targeting the RNAi system represents a novel therapeutic strategy that has the ability to intercede with multiple disease-related genes and so target many human diseases. Recently, the design of small interfering RNA (siRNA)-selective compounds has become more straightforward because of the significant progress made in predictive modeling. Exciting new data show that siRNA blocks gene function in vivo, suggesting that it has potential as a therapeutic approach for humans. This article highlights recent advances in siRNA research and discusses the aims of the pharmaceutical and biotechnology industries to progress siRNA compounds into the clinical. In the fight against disease, the use of RNAi is a powerful new tactic that adds to the arsenal of small-molecule inhibitors and antibody-blocking approaches.