Currently, the majority of the population has been vaccinated against COVID‐19 and/or has experienced SARS‐CoV‐2 infection either before or after vaccination. The immunological response to repeated ...episodes of infections is not completely clear. We measured SARS‐CoV‐2 specific neutralization titers by a pseudovirus assay after BA.1 infection and RBD‐specific immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) in a cohort of COVID‐19 uninfected and triple vaccinated individuals (breakthrough infection group, BTI) as compared with those previously infected by SARS‐CoV‐2 (reinfection group, REI) who underwent identical vaccination schedule. SARS‐CoV‐2 specific neutralizing response after BA.1 infection was significantly higher in the BTI group as compared with the REI. Furthermore, neutralization titers in REI were not significant different from convalescent non reinfected controls. RBD‐specific IgG and IgA, but not IgM, were also significantly higher in BTI as compared with REI. Our results show that the first episode of SARS‐CoV‐2 infection induces a significant increase in neutralizing titers in triple vaccinated individuals and that previous SARS‐CoV‐2 infection compromise significantly the neutralization response induced by reinfection, even by divergent SARS‐CoV‐2 variants and at least up to 2 years postinfection, suggesting a fundamental limitation in inducing effective booster through the intranasal route in previously infected individuals.
The efficient spread of SARS-CoV-2 resulted in a pandemic that is unique in modern history. Despite early identification of ACE2 as the receptor for viral spike protein, much remains to be understood ...about the molecular events behind viral dissemination. We evaluated the contribution of C-type lectin receptors (CLR S ) of antigen-presenting cells, widely present in air mucosa and lung tissue. DC-SIGN, L-SIGN, Langerin and MGL bind to diverse glycans of the spike using multiple interaction areas. Using pseudovirus and cells derived from monocytes or T-lymphocytes, we demonstrate that while virus capture by the CLRs examined does not allow direct cell infection, DC/L-SIGN, among these receptors, promote virus transfer to permissive ACE2+ cells. A glycomimetic compound designed against DC-SIGN, enable inhibition of this process. Thus, we described a mechanism potentiating viral capture and spreading of infection. Early involvement of APCs opens new avenues for understanding and treating the imbalanced innate immune response observed in COVID-19 pathogenesis
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A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were ...effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC50 value of 0.41 ± 0.13 μM, almost five times lower than the IC50 obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC50 = 0.85 ± 0.18 μM) but less potent than raltegravir (IC50 = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2,4(1H,3H)-diones as useful leads for further optimization.
Despite the efforts to develop new treatments against Ebola virus (EBOV) there is currently no antiviral drug licensed to treat patients with Ebola virus disease (EVD). Therefore, there is still an ...urgent need to find new drugs to fight against EBOV. In order to do this, a virtual screening was done on the druggable interaction between the EBOV glycoprotein (GP) and the host receptor NPC1 with a subsequent selection of compounds for further validation. This screening led to the identification of new small organic molecules with potent inhibitory action against EBOV infection using lentiviral EBOV-GP-pseudotype viruses. Moreover, some of these compounds have shown their ability to interfere with the intracellular cholesterol transport receptor NPC1 using an ELISA-based assay. These preliminary results pave the way to hit to lead optimization programs that lead to successful candidates.
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•Actually there is no antiviral drugs to treat patients with Ebola virus disease.•The interaction between EBOV glycoprotein (GP) and the host receptor NPC1 is a well-known druggable target.•Virtual screening on this interaction allowed us the selection of candidates for experimental validation.•Identification of new small molecules able to inhibit EBOV infection using lentiviral EBOV-GP-pseudotype viruses.
Novel safe, immunogenic, and effective vaccines are needed to control the COVID-19 pandemic, caused by SARS-CoV-2. Here, we describe the safety, robust immunogenicity, and potent efficacy elicited in ...rhesus macaques by a modified vaccinia virus Ankara (MVA) vector expressing a full-length SARS-CoV-2 spike (S) protein (MVA-S). MVA-S vaccination was well tolerated and induced S and receptor-binding domain (RBD)-binding IgG antibodies and neutralizing antibodies against SARS-CoV-2 and several variants of concern. S-specific IFNγ, but not IL-4, -producing cells were also elicited. After SARS-CoV-2 challenge, vaccinated animals showed a significant strong reduction of virus loads in bronchoalveolar lavages (BAL) and decreased levels in throat and nasal mucosa. Remarkably, MVA-S also protected macaques from fever and infection-induced cytokine storm. Computed tomography and histological examination of the lungs showed reduced lung pathology in MVA-S-vaccinated animals. These findings favor the use of MVA-S as a potential vaccine for SARS-CoV-2 in clinical trials.
•Ebola virus neutralizing response increases long after recovery in convalescent patients.•Neutralizing titers are higher against the current Makona variant of EBOV.•Convalescent plasma from Ebola ...infection should be tested for neutralizing titer.
The current outbreak of Ebola Virus Disease in West Africa is caused by a new variant of Ebola virus (EBOV) named Makona 2014, whose sequence differs 3% from isolates from Central Africa such as Mayinga 1976 EBOV. The specificity and kinetics of the neutralizing antibody response induced by the circulating Makona EBOV has not been thoroughly studied.
We have used a lentiviral EBOV-glycoprotein (GP)-pseudotyped infection assay to measure Makona-GP and Mayinga-GP specific neutralizing activity of plasma from three convalescent Ebola Virus Disease patients from the current EBOV outbreak at 2, 3, 4 and 9 months post-infection. Total anti-EBOV GP IgG was measured by a commercial ELISA assay.
In convalescent Ebola Virus Disease patients, Makona-GP-specific neutralizing titers increased from 2 months (mean IC50 1/59), 3 months (IC50 1/212), 4 months (IC50 1/239) and up to 9 months (IC50 1/268) post-infection. Neutralizing activity of plasma from the three convalescent Ebola Virus Disease patients was more vigorous against the current Makona-GP pseudotyped EBOV variant than against Mayinga-GP pseudotyped EBOV and this difference was observed at each time point tested: Mayinga vs Makona mean IC50 fold=4.92 at 2 months post-infection, 2.89 fold at 3 months post-infection, 2.23 at 4 months post-infection and 2.98 at 9 months post-infection (all differences p<0.01). Total level of IgG against EBOV-GP did not evolve significantly during the follow up.
In convalescent Ebola Virus Disease patients, EBOV-GP specific neutralizing activity increases over time, at least up to 9 months post-infection, which suggests that active affinity maturation of antibodies takes place long after clinical recovery. EBOV-GP specific neutralizing response is significantly higher against Makona EBOV circulating in West Africa than against the variants included in the currently approved vaccines. Correlates of protection for EBOV vaccines have not been completely established and the relevance of a lower neutralizing activity in convalescent plasma from the current outbreak against one of the EBOV-GPs contained in the vaccines in terms of its potential efficacy does not necessarily preclude its efficacy. However, this observation highlights the concern regarding the natural diversity of EBOV and its subsequent challenge for diagnosis, therapy and vaccine design. EBOV-GP neutralizing activity varies considerably over time in convalescent Ebola Virus Disease patients. Titering of convalescent blood products would be desirable to standardize and evaluate their potential therapeutic value.
Human immunodeficiency virus (HIV) reverse transcriptase (RT)‐associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. ...In this work, we report the design, synthesis, and biologic evaluation of a novel series of galloyl derivatives with HIV‐1 RNase H inhibitory activity. Most of them showed IC50s at sub‐ to low‐micromolar concentrations in enzymatic assays. The most potent compound was II‐25 that showed an IC50 of 0.72 ± 0.07 μM in RNase H inhibition assays carried out with the HIV‐1BH10 RT. II‐25 was 2.8 times more potent than β‐thujaplicinol in these assays. Interestingly, II‐25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure–activity relationships (SAR) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds.
A series of galloyl derivatives was designed and synthesized as anti‐HIV‐1 RNase H inhibitors, the most potent compound of which showed an IC50 of 0.72 ± 0.07 μM, 2.8 times more potent than β‐thujaplicinol. SAR studies and molecular modeling analysis provided helpful insight for further optimization of selected compounds.
The development of compounds with strong affinity for the receptor DC-SIGN is a topic of remarkable interest due to the role that this lectin plays in several pathogen infection processes and in the ...modulation of the immune response. DC-SIGN recognizes mannosylated and fucosylated oligosaccharides in a multivalent manner. Therefore, multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. We have previously demonstrated that linear pseudodi- and pseudotrisaccharides are adequate ligands for DC-SIGN. In this work, we show that multivalent presentations of these glycomimetics based on polyester dendrons and dendrimers lead to very potent inhibitors (in the nanomolar range) of cell infection by Ebola pseudotyped viral particles by blocking DC-SIGN receptor. Furthermore, SPR model experiments confirm that the described multivalent glycomimetic compounds compete in a very efficient manner with polymannosylated ligands for binding to DC-SIGN.
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