Characterization of new synthetic or natural compounds with broad spectrum or dual antiviral activity in HIV-1 treatment

In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Development of inhibitors that operate by a novel mechanism of action could expand the options for clinicians to address these unmet medical needs for the HIV-1-infected patient population or could represent novel options for an effective prevention. In this contest, one possibility is the development of single drug with multiple targets binding, such as the natural compound kuwanon-L. Derived from the computational identification of novel potential allosteric inhibitors of HIV integrase, in this thesis kuwanon-L has been further characterised in enzymatic assays to evaluate its activity in vitro. Moreover, kuwanon-L was tested in cellular-based assays to confirm its antiviral activity also on viral strains. Finally, its mechanism of action was further investigated through a time-of-addition (TOA) experiment and its innovative dual mode of action on both HIV integrase and reverse transcriptase was confirmed in enzymatic assays. On the other hand, compounds with novel mechanisms of action and targeting very early steps of viral life cycle, as the novel series of rhodanine derivatives investigated in the second part of this work, may represent potent anti-HIV-1 agents suitable for prevention approaches. Their activity not only on HIV but also on other sexually transmitted infections such as HSV-1/2 viruses, and their favourable pharmacokinetic profile further emphasize their usage as topical microbicides in pre-exposure prophylaxis (PrEP) approaches

Characterization of new synthetic or natural compounds with broad spectrum or dual antiviral activity in HIV-1 treatment

In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Development of inhibitors that operate by a novel mechanism of action could expand the options for clinicians to address these unmet medical needs for the HIV-1-infected patient population or could represent novel options for an effective prevention. In this contest, one possibility is the development of single drug with multiple targets binding, such as the natural compound kuwanon-L. Derived from the computational identification of novel potential allosteric inhibitors of HIV integrase, in this thesis kuwanon-L has been further characterised in enzymatic assays to evaluate its activity in vitro. Moreover, kuwanon-L was tested in cellular-based assays to confirm its antiviral activity also on viral strains. Finally, its mechanism of action was further investigated through a time-of-addition (TOA) experiment and its innovative dual mode of action on both HIV integrase and reverse transcriptase was confirmed in enzymatic assays. On the other hand, compounds with novel mechanisms of action and targeting very early steps of viral life cycle, as the novel series of rhodanine derivatives investigated in the second part of this work, may represent potent anti-HIV-1 agents suitable for prevention approaches. Their activity not only on HIV but also on other sexually transmitted infections such as HSV-1/2 viruses, and their favourable pharmacokinetic profile further emphasize their usage as topical microbicides in pre-exposure prophylaxis (PrEP) approaches

Characterization of new synthetic or natural compounds with broad spectrum or dual antiviral activity in HIV-1 treatment

In recent years many advances have been made in the fight against HIV-1 infection. However, the lack of a vaccine, together with the increasing resistance to the highly active anti-retroviral therapy (HAART), make HIV-1 infection still a serious global emergency. Development of inhibitors that operate by a novel mechanism of action could expand the options for clinicians to address these unmet medical needs for the HIV-1-infected patient population or could represent novel options for an effective prevention. In this contest, one possibility is the development of single drug with multiple targets binding, such as the natural compound kuwanon-L. Derived from the computational identification of novel potential allosteric inhibitors of HIV integrase, in this thesis kuwanon-L has been further characterised in enzymatic assays to evaluate its activity in vitro. Moreover, kuwanon-L was tested in cellular-based assays to confirm its antiviral activity also on viral strains. Finally, its mechanism of action was further investigated through a time-of-addition (TOA) experiment and its innovative dual mode of action on both HIV integrase and reverse transcriptase was confirmed in enzymatic assays. On the other hand, compounds with novel mechanisms of action and targeting very early steps of viral life cycle, as the novel series of rhodanine derivatives investigated in the second part of this work, may represent potent anti-HIV-1 agents suitable for prevention approaches. Their activity not only on HIV but also on other sexually transmitted infections such as HSV-1/2 viruses, and their favourable pharmacokinetic profile further emphasize their usage as topical microbicides in pre-exposure prophylaxis (PrEP) approaches

The role of infections and coinfections with newly identified and emerging respiratory viruses in children

<p>Abstract</p> <p>Acute respiratory infections are a major cause of morbidity in children both in developed and developing countries. A wide range of respiratory viruses, including respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza viruses (PIVs), adenovirus, rhinovirus (HRV), have repeatedly been detected in acute lower respiratory tract infections (LRTI) in children in the past decades. However, in the last ten years thanks to progress in molecular technologies, newly discovered viruses have been identified including human Metapneumovirus (hMPV), coronaviruses NL63 (HcoV-NL63) and HKU1 (HcoV-HKU1), human Bocavirus (HBoV), new enterovirus (HEV), parechovirus (HpeV) and rhinovirus (HRV) strains, polyomaviruses WU (WUPyV) and KI (KIPyV) and the pandemic H1N1v influenza A virus. These discoveries have heavily modified previous knowledge on respiratory infections mainly highlighting that pediatric population is exposed to a variety of viruses with similar seasonal patterns. In this context establishing a causal link between a newly identified virus and the disease as well as an association between mixed infections and an increase in disease severity can be challenging. This review will present an overview of newly recognized as well as the main emerging respiratory viruses and seek to focus on the their contribution to infection and co-infection in LRTIs in childhood.</p

Epidemiological, molecular and clinical features of enterovirus 109 infection in children and in adult stem cell transplant recipients

A novel human enterovirus (HEV) type within the species HEV-C, named EV109, was discovered from cases of respiratory illness in Nicaragua in September 2010. The aim of this study, was to retrospectively examine the presence and the role of EV109 in respiratory samples from two patients populations; infants below the age of 2 years, hospitalized for acute respiratory diseases (ARDs) and adult hematopoietic stem cell transplantation recipients

Infection and Coinfection of Human Rhinovirus C in Stem Cell Transplant Recipients

In 54 adult stem cell transplant recipients, the presence and persistence of human rhinoviruses (including the novel lineage C) were evaluated by molecular detection and phylogenetic analysis, independently from respiratory symptoms. In the same group of patients, the presence of other coinfecting respiratory pathogens, including the novel enterovirus 109, was also evaluated

Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation

Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization. Immunized mice had reduced serum cytokine levels, reduced insulin and fasting glucose concentrations; and gene expression in both liver and visceral adipose tissue confirmed a reduced inflammatory steady-state after immunization. Moreover, both gut and atherosclerotic plaques of immunized mice showed reduced inflammatory cells and an increased M2 macrophage fraction. These results suggest that adaptive responses directed against microbes present in our microbiota have systemic beneficial consequences and demonstrate the key role of apoE in this mechanism that could be exploited to treat immune-metabolic diseases

Legislative Documents

Also, variously referred to as: House bills; House documents; House legislative documents; legislative documents; General Court documents

Prenylated phloroglucinols from Hypericum scruglii, an endemic species of Sardinia (Italy), as new dual HIV-1 inhibitors effective on HIV-1 replication

In a search for new potential multitarget anti-HIV compounds from natural products, we have identified in Hypericum scruglii, an endemic and exclusive species of Sardinia (Italy), a potent plant lead. The phytochemical study of the hydroalcoholic extract obtained from its leaves led to the isolation of its most abundant secondary metabolites, belonging to different chemical classes. In particular, three phloroglucinols derivatives were identified, confirming their significance as chemotaxonomic markers of the Hypericum genus. Among them, the 3-(13-hydroxygeranyl)-1-(2'-methylbutanoyl)phloroglucinol was reported here for the first time. All six isolated compounds have been evaluated firstly for the inhibition of both Human Immunodeficiency Virus type 1 (HIV-1) Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities, for the inhibition of HIV-1 integrase (IN) in biochemical assays, and also for their effect on viral replication. Among the isolated metabolites, three phloroglucinol derivatives and quercitrin were effective on both RT-associated RDDP and RNase H activities in biochemical assays. The same active compounds affected also HIV-1 IN strand transfer function, suggesting the involvement of the RNase H active site. Furthermore, phloroglucinols compounds, included the newly identified compound, were able to inhibit the HIV-1 replication in cell based assays

2-Aminothiazolones as anti-hiv agents that act as gp120-cd4 inhibitors

We report here the synthesis of 2-aminothiazolones along with their biological properties as novel anti-HIV agents. Such compounds have proven to act through the inhibition of the gp120-CD4 protein-protein interaction that occurs at the very early stage of the HIV-1 entry process. No cytotoxicity was found for these compounds, and broad antiviral activities against laboratory strains and pseudotyped viruses were documented. Docking simulations have also been applied to predict the mechanism, at the molecular level, by which the inhibitors were able to interact within the Phe43 cavity of HIV-1 gp120. Furthermore, a preliminary absorption, distribution, metabolism, and excretion (ADME) evaluation was performed. Overall, this study led the basis for the development of more potent HIV entry inhibitors