Designing Inhibitors for the SARS CoV Main Protease as Anti-SARS Drugs

Severe Acute Respiratory Syndrome (SARS) is a serious respiratory illness reported in parts of Asia and Canada. A novel coronavirus (CoV) has been isolated and identified as the cause of the SARS for which there is currently no effective treatment. Given the epidemic, the rapid development of efficacious antiviral drugs is needed. The key replicative enzyme SARS CoV main protease (Mpro) represents an attractive target for antiviral chemotherapy. Detailed structural study of the substrate binding cavity led to the generation of a 3-D pharmacophore. Subsets of chemical structures were extracted from the commercial databases by using the defined pharmacophore. Compound mapping to the pharmacophore were docked into the substrate-binding cavity and scored. The selected chemicals were assayed against the SARS CoV Mpro for their inhibitory activity. Three of the compounds showed significant inhibition of the SARS CoV Mpro at low micromolar concentration. This study provides potential lead compounds for specific SARS CoV protease inhibitors. It also signifies the utility of computational techniques for rapid discovery of inhibitors for novel targets.

A Wider Range of Conditions Contributing to Death in a Cohort of People Who Have Injected Drugs. Findings from an Edinburgh Cohort.

BackgroundThe morbidity and mortality attributed to injecting drug use is a substantial contributor to any study on causes of premature death. Understanding the extent of this may be limited by difficulties in observing and recording outcomes over several decades. Historic studies have recorded information in a period when blood borne virus and drug deaths were a smaller proportion or, in the cases of Hepatitis C and HIV/AIDS, absent from National mortality figures.Design and settingA cohort of people who had, ever, injected drugs was established over a prolonged period of observation in one, community based, medical practice in Edinburgh (UK). Outcomes were measured in the clinical situation and by accessing death certificates from national, UK, registers.FindingsCauses of death in a cohort of 794 people who inject drugs (PWIDs) varied over time, some conditions relating to single pathological diagnoses and others were more complicated, multimorbid, and cumulative over time. HIV/AIDS was a striking cause of death until 1995 when antiviral chemotherapy was introduced. Drug related deaths (mainly overdose) remained a significant cause of death and death due to alcohol, respiratory, cardiovascular and cancer (mainly lung) increased over time. A wide range of other causes including suicide and violence and trauma were recorded.ConclusionsMortality resulting from present or historic drug use may be underestimated in current recoding systems, which largely record deaths from overdose or a single pathological event in an acute situation. The range of conditions causing or contributing to premature death is enormous reflecting multiple risks associated with drug use.

I CHEMIOTERAPICI ANTIVIRALI1

The concept of drug development with specific antiviral action is quite recent. The discovery, in the late ‘70s, that acyclic nucleoside analogs could inhibit the replication of the Herpes Simplex virus (HSV) DNA, was the fundamental step that opened the way to the research on drugs able to deal with diseases caused by viruses. In the ‘80s, the need to fight another disease related to a virus, AIDS caused by HIV, gave a further boost to the research in the field of viral chemotherapy. Currently, several classes of drugs are available for the treatment of viruses such as influenza virus, respiratory syncytial virus, herpes simplex virus, varicella-zoster virus, HBV and hepatitis viruses, cytomegalovirus and HIV. Nevertheless, we however need a continuous and progressive development of antiviral chemotherapy and of the research related to it that can cope with the problem of the effectiveness of antiviral vaccines, the emergence of new diseases related to immunosuppression. In this context, the research of professor Paolo Mantegazza has made a valuable contribution to the understanding of the transforming role of some viruses such as polyomaviruses, including the SV40 monkey vacuolar virus. Professor Mantegazza also made a significant contribution to the synthesis of compounds for transmissible spongiform encephalopathies caused by prions. 1Trascrizione non corretta dall’Autore.

Drug repurposing for yellow fever using high content screening

ABSTRACTBackgroundYellow fever is an acute febrile illness caused by a mosquito-borne flavivirus. The discovery that mosquitos were responsible for transmission and that the disease was preventable by vector control, as well as the development of an efficacious vaccine (in the 1930s) have reduced its public health impact. However, underutilization of vaccination and discontinuation of vector control measures have led to yellow fever outbreaks, affecting thousands of people in Africa and South America, and is a continued threat to people who travel to endemic regions without vaccination. An additional concern is that the vaccine has important contraindications, and the currently available doses are insufficient to immunize the populations under risk of contracting yellow fever. Specific antiviral chemotherapy would be an alternative to vaccination, however there is none yet available. Drug repurposing is one strategy that can speed up drug discovery and development and has been underexplored for yellow fever.MethodsA high content screening assay for the discovery of anti-yellow fever compounds was developed and used to screen a library of pharmacologically compounds, which includes approved drugs and covers most signalling pathways and all major drug target classes. The same library was screened against cells infected with a serotype 2 of the dengue virus.Results and conclusionFrom 1280 compounds screened, 88 compounds (6,9% of the library) were found to reduce yellow fever virus (YFV) infection in 50% or more. Interestingly, the number of compounds that presented similar activity against dengue (DENV) infection was considerably lower (18 compounds, 1,4%). Among these, 12 compounds were active against both viruses, highlighting the potential of finding compounds with broad antiviral activity in diversity libraries. The top 27 anti-YFV compounds were selected for further activity determination in dose-response. Five compounds (Gant61, benztropine mesylate, brequinar sodium salt hydrate, PF-429242 dihydrochloride and U-73343) presented selective activity against YFV infection in a human cell line, but only two of them, brequinar and U-73343, were also active against DENV. These compounds, which represent a broad spectrum of pharmacological functions, have not been previously described as having anti-YFV activity, thus offering a valuable opportunity for the development of specific antiviral chemotherapy for yellow fever.

INFLUENCE OF IMMUNOMODULATORY DRUG STIMFORTE ON THE EXPERIMENTAL HERPES VIRUS INFECTION IN COMBINATION WITH ACYCLOVIR AND ON HIV-INFECTION IN COMBINATION WITH RETROVIR

The combined action of the immunostimulatory drug Stimforte and the basic etiotropic drug acyclovir commonly used to treat herpes infections was studied using the model of lethal experimental infection of mice BALB/c with herpes simplex virus type 1. It was found that the interaction of these drugs is additive. In addition, Stimforte inhibits infection caused by a strain of virus, which is highly resistant to acyclovir. When administered 24 hours prior to HIV-1 infection of human lymphoblastoid cells MT-4, Stimforte exhibited reliable antiretroviral activity best expressed during the early period of infection (the 3rd day). On the 6th day of observation the effect was almost completely lost. Combined use of Stimforte at a dose of 50-100 µg/ml with a subthreshold dose of retrovir (0.03 µg/ml) had a synergistic antiviral effect. Thus, Stimforte, which exhibits, on the one hand, antiviral activity against viruses of different families and, on the other hand, the immunomodulatory properties, could be promising as an etiopathogenic tool in helping to normalize both nonspecific and specific immunity. It may be used simultaneously with etiotropic antiviral chemotherapy in treatment of generalized herpes infection in patients with immunodeficiency. Furthermore, Stimforte can be used in the case of development of drug resistance in HSV, in particular, in HIV-infected patients.

Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library

Background The recent epidemics of Zika virus (ZIKV) implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account. Thus, antiviral chemotherapy should be pursued as a priority strategy to control the spread of the virus and prevent the complications associated with Zika. Methods Here we describe a fast and reliable cell-based, high-content screening assay for discovery of anti-ZIKV compounds. This methodology has been used to screen the National Institute of Health Clinical Collection compound library, a small collection of FDA-approved drugs. Results and conclusion From 725 FDA-approved compounds triaged, 29 (4%) were found to have anti-Zika virus activity, of which 22 had confirmed (76% of confirmation) by dose-response curves. Five candidates presented selective activity against ZIKV infection and replication in a human cell line. These hits have abroad spectrum of chemotypes and therapeutic uses, offering valuable opportunities for selection of leads for antiviral drug discovery.

Efficacy of antiviral chemotherapy for retrovirus-infected cats

Global importance:The two feline retroviruses, feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV), are global and widespread, but differ in their potential to cause disease.Viral infection – FIV:FIV, a lentivirus that shares many properties with human immunodeficiency virus (HIV), can cause an acquired immune deficiency syndrome, which predisposes cats to other infections, stomatitis, neurological disorders and tumours. Although secondary infections are common, specific opportunistic infections or acquired immunodeficiency virus-defining infections, such as those that occur with HIV, are not commonly reported in FIV-infected cats. In most naturally infected cats, FIV does not cause a severe clinical syndrome; with appropriate care, FIV-infected cats can live many years before succumbing to conditions unrelated to their FIV infection. Thus, overall survival time is not necessarily shorter than in uninfected cats, and quality of life is usually high over many years or lifelong.Viral infection – FeLV:FeLV, an oncornavirus, is more pathogenic than FIV. Historically, it was considered to account for more disease-related deaths and clinical syndromes in cats than any other infectious agent. Recently, the prevalence and importance of FeLV have been decreasing, mainly because of testing and eradication programmes and the use of FeLV vaccines. Progressive FeLV infection can cause tumours, bone marrow suppression and immunosuppression, as well as neurological and other disorders, and leads to a decrease in life expectancy. However, with appropriate care, many FeLV-infected cats can also live several years with a good quality of life.Practical relevance:A decision regarding treatment or euthanasia should never be based solely on the presence or absence of a retrovirus infection. Antiviral chemotherapy is of increasing interest in veterinary medicine, but is still not used commonly.Evidence base:This article reviews the current literature on antiviral chemotherapy in retrovirus-infected cats, focusing on drugs that are currently available on the market and, thus, could potentially be used in cats.