Antiviral | EPFL Graph Search

Un antiviral est une molécule perturbant le cycle de réplication d'un ou de plusieurs virus, permettant ainsi de ralentir mais rarement d'arrêter une infection virale. Avec les vaccins et la prévention, ils constituent le seul moyen connu pour lutter contre les infections d'origines virales. Les antiviraux sont efficaces pour lutter contre les virus en attendant la mise au point d'un vaccin, qui est la seule manière connue d'éradiquer un virus à long terme, comme l'ont montré les différentes campagnes d'éradication de la poliomyélite et surtout de la variole. Un antirétroviral est une classe particulière d'antiviral destinée à lutter contre les rétrovirus. Action Un antiviral agit en perturbant chimiquement un moment précis du cycle de réplication d'un virus. Il freine ainsi l'infection en limitant la multiplication des particules virales. Pour améliorer l'action des antiviraux, certains traitements prescrivent des médicaments stimulant la réaction du système immunitaire

Novel broad-spectrum virucidal antivirals

Matteo Gasbarri

The current COVID-19 pandemic has showed the threats that viruses can cause to the whole world. Over 200 million infections and over 4.5 million deaths and enormous socio-economic impact were the output of the emergence of a single new pathogen: SARS-CoV-2. The development of vac-cines is the paramount solution to overcome the pandemic. However, even with extraordinary and unprecedented worldwide efforts, it took almost one year to have a first validated vaccine and it will take longer to have a global vaccination. In addition, vaccines are preventive drugs, that need to be administered before the infection to stimulate the immune-system of the patient. In the meanwhile, in case of an infection, we were harmless in the fight against the virus.Antivirals are curative drugs, that inhibit one step of the viral replication. Many approaches have been investigated: antibodies, peptides, peptomimics, small molecules. Most of them are specif-ic to a single family of virus, making the development slow and expensive. Entry inhibitors are a class of antivirals that binds to the virus, preventing the attachment to the cell membrane. Such antivirals usually have a broad-spectrum of action, since they mimic cell receptors, such as heparan sulfate pro-teoglycans (HSPGs), exploited by different viruses. Many compounds have been developed throughout the years; however, the reversible nature of the virus inhibition mechanism has prevented their trans-lation to the clinic. Our group has recently shown that the simple addition of a long hydrophobic linker makes the inhibition irreversible, proving this hypothesis with two compounds: gold-nanoparticles and beta-cyclodextrins. The goal of this thesis is to develop novel antivirals able to inhibit a broad-spectrum of viruses with an irreversible mechanism of action and to investigate the key features responsible of such properties. In this thesis, we further expand the broad-spectrum activity of gold-nanoparticles and beta-cyclodextrins showing that they are capable of inhibiting viruses beyond HSPG-dependent ones. In addition, we show their ability of reversibly inactivating SARS-CoV-2. Moreover, we have investigated the role of the hydrophobic linker's length in the virucidal inhibition in case of cyclodextrins, proving the need of such moiety to have an irreversible viral inactivation. Envisioning a translation of such drug, we have performed a preliminar pharmacokinetic study performed via intranasal administration.A novel class of compounds has been also proposed: sulfated/sulfonated dendritic polyglyc-erol. A broad investigation of the molecular design rules needed to achieve nanomolar irreversible viral inhibition is discussed. We also show that the most active compound proves to be active against HSV-2 and RSV, thus with a broad-spectrum activity. In addition, we demonstrate that the virucidal activity is leading to the release of viral DNA upon interaction between the virus and our dendritic polyglycerol. A different modification of dendritic polyglycerol, bearing carboxylic acid, showed activi-ty against SARS-CoV-2; such inhibition results to be irreversible. This compound has been further test-ed in a hamster model, where initial studies confirm its feasibility as antiviral. In addition to these studies on development of virucidal antivirals, different technological so-lutions to prevent viral spreading are proposed. In particular, we focused on an antiviral filter and antiviral surfaces.

EPFL2021

Virucidal nanomaterials against influenza

Özgün Kocabiyik

Influenza affects millions of people in all parts of the world. The fact that influenza virus can spread through air increases the chance of influenza outbreaks. There are 3 to 5 million severe cases of influenza resulting in 290,000 to 650,000 deaths every year. Not as common as outbreaks, but in the 20th century four influenza pandemics appeared: Spanish influenza (1918, 50 million deaths), Asian influenza (1957, 2 million deaths), Hong Kong influenza (1968, 1 million deaths) and swine influenza pandemic (2009, 150,000 to 500,000 deaths). World health organization (WHO) emphasizes that influenza is the only pathogen that has a reasonable chance of causing a new pandemic in the near future. It is unlikely that current influenza vaccines and therapeutics will be sufficient to prevent a coming pandemic. Presented within this thesis is a novel approach to irreversibly inhibit influenza virus with non-toxic and highly effective nanomaterials. These nanomaterials are designed so to bear glycan end-groups that bind to the influenza virus with high-affinity. Their design is such that binding determines a chain of events that leads to the irreversible loss of viral infectivity (i.e. virucidal mechanism). There are two key elements in the design of these materials. The first is the correct glycan sequence, terminating with sialic acid, needed to bind with high affinity to the influenza virus attachment ligand that is hemagglutinin. The second is a certain hydrophobic content in the drug, needed to impart the irreversibility in the antiviral effect. We show that when both elements are present, a virucidal non-toxic drug can be achieved either with gold nanoparticles or with cyclodextrins. With these materials several human influenza strains of type A and B were inhibited with virucidal mechanism. Furthermore, ex-vivo and in-vivo antiviral activity of the nanomaterials with cyclodextrin core was investigated against a very aggressive influenza A strain. Ex-vivo studies clearly demonstrated that the mechanism of inhibition is virucidal. In the in-vivo studies, nanomaterials prevented the mice to loose weight and body temperature; significantly reduced the virus concentration in the lungs and in the nose. These materials can be further developed to target animal strains of the influenza virus. This is particularly important since influenza pandemics usually appear when humans are infected with a new animal strain such as avian and swine influenza.

EPFL2019

Advances in the development of entry inhibitors for sialic-acid-targeting viruses

Matteo Gasbarri, Özgün Kocabiyik, Francesco Stellacci

Over the past decades, several antiviral drugs have been developed to treat a range of infections. Yet the number of treatable viral infections is still limited, and resistance to current drug regimens is an ever-growing problem. Therefore, additional strategies are needed to provide a rapid cure for infected individuals. An interesting target for antiviral drugs is the process of viral attachment and entry into the cell. Although most viruses use distinct host receptors for attachment to the target cell, some viruses share receptors, of which sialic acids are a common example. This review aims to give an update on entry inhibitors for a range of sialic-acidtargeting viruses and provides insight into the prospects for those with broad-spectrum potential.

ELSEVIER SCI LTD2021