Exploration of potential inhibitors for SARS-CoV-2 Mpro considering its mutants via structure-based drug design, molecular docking, MD simulations, MM/PBSA, and DFT calculations.

The main protease (Mpro) of SARS-COV-2 plays a vital role in the viral life cycle and pathogenicity. Due to its specific attributes, this 3-chymotrypsin like protease can be a reliable target for the drug design to combat COVID-19. Since the advent of COVID-19, Mpro has undergone many mutations. Here, the impact of 10 mutations based on their frequency and five more based on their proximity to the active site was investigated. For comparison purposes, the docking process was also performed against the Mpros of SARS-COV and MERS-COV. Four inhibitors with the highest docking score (11b, α-ketoamide 13b, Nelfinavir, and PF-07321332) were selected for the structure-based ligand design via fragment replacement, and around 2000 new compounds were thus obtained. After the screening of these new compounds, the pharmacokinetic properties of the best ones were predicted. In the last step, comparative molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area calculations (MM/PBSA), and density functional theory calculations were performed. Among the 2000 newly designed compounds, three of them (NE1, NE2, and NE3), which were obtained by modifications of Nelfinavir, showed the highest affinity against all the Mpro targets. Together, NE1 compound is the best candidate for follow-up Mpro inhibition and drug development studies.

An overview of the vaccine platforms to combat COVID-19 with a focus on the subunit vaccines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that has caused the recent coronavirus disease (COVID-19) global pandemic. The current approved COVID-19 vaccines have shown considerable efficiency against hospitalization and death. However, the continuation of the pandemic for more than two years and the likelihood of new strain emergence despite the global rollout of vaccination highlight the immediate need for the development and improvement of vaccines. mRNA, viral vector, and inactivated virus vaccine platforms were the first members of the worldwide approved vaccine list. Subunit vaccines. which are vaccines based on synthetic peptides or recombinant proteins, have been used in lower numbers and limited countries. The unavoidable advantages of this platform, including safety and precise immune targeting, make it a promising vaccine with wider global use in the near future. This review article summarizes the current knowledge on different vaccine platforms, focusing on the subunit vaccines and their clinical trial advancements against COVID-19.

In silico design of a multi-epitope vaccine against the spike and the nucleocapsid proteins of the Omicron variant of SARS-CoV-2.

Computational studies can comprise an effective approach to treating and preventing viral infections. Since 2019, the world has been dealing with the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most important achievement in this short period of time in the effort to reduce morbidity and mortality was the production of vaccines and effective antiviral drugs. Although the virus has been significantly suppressed, it continues to evolve, spread, and evade the host's immune system. Recently, researchers have turned to immunoinformatics tools to reduce side effects and save the time and cost of traditional vaccine production methods. In the present study, an attempt has been made to design a multi-epitope vaccine with humoral and cellular immune response stimulation against the Omicron variant of SARS-CoV-2 by investigating new mutations in spike (S) and nucleocapsid (N) proteins. The population coverage of the vaccine was evaluated as appropriate compared to other studies. The results of molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) calculations predict the stability and proper interaction of the vaccine with Toll-like receptor 4 (TLR-4) as an innate immune receptor. The results of the immune simulation show a significant increase in the coordinated response of IgM and IgG after the third injection of the vaccine. Also, in the continuation of the research, spike proteins from BA.4 and BA.5 lineages were screened by immunoinformatics filters and effective epitopes were suggested for vaccine design. Despite the high precision of computational studies, in-vivo and in-vitro research is needed for final confirmation.Communicated by Ramaswamy H. Sarma.

Understanding the challenges to COVID-19 vaccines and treatment options, herd immunity and probability of reinfection.

Unlike pandemics in the past, the outbreak of coronavirus disease 2019 (COVID-19), which rapidly spread worldwide, was met with a different approach to control and measures implemented across affected countries. The lack of understanding of the fundamental nature of the outbreak continues to make COVID-19 challenging to manage for both healthcare practitioners and the scientific community. Challenges to vaccine development and evaluation, current therapeutic options, convalescent plasma therapy, herd immunity, and the emergence of reinfection and new variants remain the major obstacles to combating COVID-19. This review discusses these challenges in the management of COVID-19 at length and highlights the mechanisms needed to provide better understanding of this pandemic.

Tracking the pipeline: immunoinformatics and the COVID-19 vaccine design.

With the onset of the COVID-19 pandemic, the amount of data on genomic and proteomic sequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stored in various databases has exponentially grown. A large volume of these data has led to the production of equally immense sets of immunological data, which require rigorous computational approaches to sort through and make sense of. Immunoinformatics has emerged in the recent decades as a field capable of offering this approach by bridging experimental and theoretical immunology with state-of-the-art computational tools. Here, we discuss how immunoinformatics can assist in the development of high-performance vaccines and drug discovery needed to curb the spread of SARS-CoV-2. Immunoinformatics can provide a set of computational tools to extract meaningful connections from the large sets of COVID-19 patient data, which can be implemented in the design of effective vaccines. With this in mind, we represent a pipeline to identify the role of immunoinformatics in COVID-19 treatment and vaccine development. In this process, a number of free databases of protein sequences, structures and mutations are introduced, along with docking web servers for assessing the interaction between antibodies and the SARS-CoV-2 spike protein segments as most commonly considered antigens in vaccine design.

Health economics matters in the nanomaterial world: Cost-effectiveness of utilizing an inhalable antibacterial nanomaterial for the treatment of multidrug-resistant pneumonia

Bacterial pathogens rapidly develop resistance to clinically approved antibiotics. Together with the subsiding economic incentives for the development of newer and more effective antibiotic therapies, this threatens to cause a bacterial disease pandemic in the next 30 years. For this reason, timely analyses of various scientific and socioeconomic aspects of alternatives to traditional antibiotic therapies are needed. Here, pharmacoeconomic cost-of-illness, cost-effectiveness and price sensitivity analyses were performed to assess the impact of multidrug resistance of Pseudomonas aeruginosa implicated in pneumonia on healthcare systems of the United States and of the developing countries. The assessment was extended to include the effects of various therapies for this condition, one group of which consisted of colistin administered intravenously or with the use of a nebulizer and another therapy coming in the form of an inhalable colloidal formulation comprising biocompatible antibacterial nanoparticles. Both colistin and nanoparticle therapies produced net gain per quality adjusted life year (QALY) saved for patients with pneumonia caused by multidrug-resistant P. aeruginosa in the United States. In the developing world, in contrast, where the pricing sensitivity is shown to be higher, there is a positive cost of $8800 and $3600 per QALY saved associated with the use of colistin at a price adjusted to the local economy and administered through a parenteral route or through a nebulizer, respectively. Simultaneously, thanks to the higher affordability compensating for the 15% lower clinical efficacy assumed in the model, there is a net gain of $10,100 per QALY saved with the use of the nanoparticle formulation, translating to $52,000 gain for each life saved by the treatment. In conclusion, inorganic nanoparticle therapies for infectious disease are not only more immune to eliciting resistance than small-molecule antibiotics, but are also more applicable in low-cost healthcare systems of the developing world. The current generation of antibiotic therapies is cost-effective in high-cost healthcare systems, such as the one of the United States, but its application in more frugal settings, where pricing is as important as efficacy, comes with tremendous costs. These results demonstrate the considerable disparity in profit margin flexibility depending on the wealth and the size of the healthcare economy, which contributes daily to the widening of the gap between the rich and the poor.

Nanomedicine for the poor: a lost cause or an idea whose time has yet to come?

The most effective COVID-19 vaccines, to date, utilize nanotechnology to deliver immunostimulatory mRNA. However, their high cost equates to low affordability. Total nano-vaccine purchases per capita and their proportion within the total vaccine lots have increased directly with the GDP per capita of countries. While three out of four COVID-19 vaccines procured by wealthy countries by the end of 2020 were nano-vaccines, this amounted to only one in ten for middle-income countries and nil for the low-income countries. Meanwhile, economic gains of saving lives with nano-vaccines in USA translate to large costs in middle-/low-income countries. It is discussed how nanomedicine can contribute to shrinking this gap between rich and poor instead of becoming an exquisite technology for the privileged. Two basic routes are outlined: (1) the use of qualitative contextual analyses to endorse R&D that positively affects the sociocultural climate; (2) challenging the commercial, competitive realities wherein scientific innovation of the day operates.

COVID-19 infection and nanomedicine applications for development of vaccines and therapeutics: An overview and future perspectives based on polymersomes.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which emerged in December 2019 and caused the coronavirus disease 2019 (COVID-19) pandemic, took the world by surprise with an unprecedented public health emergency. Since this pandemic began, extraordinary efforts have been made by scientists to understand the pathogenesis of COVID-19, and to fight the infection by providing various preventive, diagnostic and treatment opportunities based on either novel hypotheses or past experiences. Despite all the achievements, COVID-19 continues to be an accelerating health threat with no specifically approved vaccine or therapy. This review highlights the recent advances in COVID-19 infection, with a particular emphasis on nanomedicine applications that can help in the development of effective vaccines or therapeutics against COVID-19. A novel future perspective has been proposed in this review based on utilizing polymersome nano-objects for effectively suppressing the cytokine storm, which may reduce the severity of COVID-19 infection.

Comparative molecular dynamics study of the receptor-binding domains in SARS-CoV-2 and SARS-CoV and the effects of mutations on the binding affinity.

Here, we report on a computational comparison of the receptor-binding domains (RBDs) on the spike proteins of severe respiratory syndrome coronavirus-2 (SARS-CoV-2) and SARS-CoV in free forms and as complexes with angiotensin-converting enzyme 2 (ACE2) as their receptor in humans. The impact of 42 mutations discovered so far on the structure and thermodynamics of SARS-CoV-2 RBD was also assessed. The binding affinity of SARS-CoV-2 RBD for ACE2 is higher than that of SARS-CoV RBD. The binding of COVA2-04 antibody to SARS-CoV-2 RBD is more energetically favorable than the binding of COVA2-39, but also less favorable than the formation of SARS-CoV-2 RBD-ACE2 complex. The net charge, the dipole moment and hydrophilicity of SARS-CoV-2 RBD are higher than those of SARS-CoV RBD, producing lower solvation and surface free energies and thus lower stability. The structure of SARS-CoV-2 RBD is also more flexible and more open, with a larger solvent-accessible surface area than that of SARS-CoV RBD. Single-point mutations have a dramatic effect on distribution of charges, most prominently at the site of substitution and its immediate vicinity. These charge alterations alter the free energy landscape, while X→F mutations exhibit a stabilizing effect on the RBD structure through π stacking. F456 and W436 emerge as two key residues governing the stability and affinity of the spike protein for its ACE2 receptor. These analyses of the structural differences and the impact of mutations on different viral strains and members of the coronavirus genera are an essential aid in the development of effective therapeutic strategies. Communicated by Ramaswamy H. Sarma.

Protecting healthcare workers during COVID-19 pandemic with nanotechnology: A protocol for a new device from Egypt.

The outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is thought to have occurred first in Wuhan, China in December 2019, before spreading to over 120 countries in the months that followed. It was declared a "public health emergency of international concern" by the World Health Organization on January 31, 2020 and recognized as a pandemic on March 11, 2020. The primary route of SARS-CoV-2 transmission from human to human is through inhalation of respiratory droplets. Devising protective technologies for stopping the spread of the droplets of aerosol containing the viral particles is a vital requirement to curb the ongoing outbreak. However, the current generations of protective respirator masks in use are noted for their imperfect design and there is a need to develop their more advanced analogues, with higher blockage efficiency and the ability to deactivate the trapped bacteria and viruses. It is likely that one such design will be inspired by nanotechnologies. Here we describe a new design from Egypt, utilizing a reusable, recyclable, customizable, antimicrobial and antiviral respirator facial mask feasible for mass production. The novel design is based on the filtration system composed of a nanofibrous matrix of polylactic acid and cellulose acetate containing copper oxide nanoparticles and graphene oxide nanosheets and produced using the electrospinning technique. Simultaneously, the flat pattern fabricated from a thermoplastic composite material is used to provide a solid fit with the facial anatomy. This design illustrates an effort made in a developing setting to provide innovative solutions for combating the SARS-CoV-2 pandemic of potentially global significance.

Why have nanotechnologies been underutilized in the global uprising against the coronavirus pandemic?

Prior research on nanotechnologies in diagnostics, prevention and treatment of coronavirus infections is reviewed. Gold nanoparticles and semiconductor quantum dots in colorimetric and immunochromatographic assays, silica nanoparticles in the polymerase chain reaction and spike protein nanospheres as antigen carriers and adjuvants in vaccine formulations present notable examples in diagnostics and prevention, while uses of nanoparticles in coronavirus infection treatments have been merely sporadic. The current absence of antiviral therapeutics that specifically target human coronaviruses, including SARS-CoV-2, might be largely due to the underuse of nanotechnologies. Elucidating the interface between nanoparticles and coronaviruses is timely, but presents the only route to the rational design of precisely targeted therapeutics for coronavirus infections. Such a fundamental approach is also a viable prophylaxis against future pandemics of this type.