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

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.

HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection

Jacques Fellay

Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B14, which protects against HIV disease progression, but the immunodominant HLA-B14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B14-EL9). A subdominant HLA-B14-restricted response targets Gag (DRYFKTLRA, HLA-B14-DA9). Using HLA-B14/peptide-saporin-conjugated tetramers, we show that HLA-B14-EL9 is substantially more potent at inhibiting viral replication than HLA-B14-DA9. HLA-B14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B14-DA9. However, these differences were HLA-B14 subtype specific, applying only to HLA-B14:02 and not to HLA-B14:01. Furthermore, the HLA-B14-associated protection against HIV disease progression is significantly greater for HLA-B14:02 than for HLA-B14:01, consistent with the superior antiviral efficacy of the HLA-B14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B14-restricted activity is substantially more efficacious than the subdominant HLA-B14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B14:02, and not HLA-B14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B14:02. Finally, we show that HLA-B14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.

American Society for Microbiology2017

Sulfonated Nanomaterials with Broad-Spectrum Antiviral Activity Extending beyond Heparan Sulfate-Dependent Viruses

Valeria Cagno, Matteo Gasbarri, Chiara Medaglia, Francesco Stellacci

Viral infections are among the main causes of death worldwide, and we lack antivirals for the majority of viruses. Heparin-like sulfated or sulfonated compounds have been known for decades for their ability to prevent infection by heparan sulfate proteoglycan (HSPG)-dependent viruses but only in a reversible way. We have previously shown that gold nanoparticles and beta-cyclodextrins coated with mercapto-undecane sulfonic acid (MUS) inhibit HSPG-dependent viruses irreversibly while retaining the low-toxicity profile of most heparin-like compounds. In this work, we show that, in stark contrast to heparin, these compounds also inhibit different strains of influenza virus and vesicular stomatitis virus (VSV), which do not bind HSPG. The antiviral action is virucidal and irreversible for influenza A virus (H1N1), while for VSV, there is a reversible inhibition of viral attachment to the cell. These results further broaden the spectrum of activity of MUS-coated gold nanoparticles and beta-cyclodextrins.

AMER SOC MICROBIOLOGY2020

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.