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1.
Biophys J ; 120(14): 2766-2770, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1603998

ABSTRACT

Understanding the structure of messenger RNA (mRNA) lipid nanoparticles, and specifically the microenvironment of the mRNA molecules within these entities, is fundamental to advancing their biomedical potential. Here, we show that a permeating cationic dye, thionine, can serve as a cryogenic electron microscopy contrasting agent by binding selectively to encapsulated mRNA without disturbing lipid nanoparticle morphology. Cryo-electron microscopy images identify the mRNA location, revealing that mRNA may exist within solvent-filled cavities or may be substantially lipid associated.


Subject(s)
Lipids , Nanoparticles , Cryoelectron Microscopy , RNA, Messenger/genetics
2.
Signal Transduct Target Ther ; 7(1): 7, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1606287

ABSTRACT

Activation-induced cytidine deaminase (AID) initiates class-switch recombination and somatic hypermutation (SHM) in antibody genes. Protein expression and activity are tightly controlled by various mechanisms. However, it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works. Here, we demonstrated that a deubiquitinase USP10, which specifically stabilizes nuclear AID protein, can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain. Interestingly, the signals from BCR and TLR1/2 synergistically promoted this phosphorylation. The deficiency of USP10 in B cells significantly decreased AID protein levels, subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or human immunodeficiency virus type 1 (HIV-1) nanoparticle vaccines. Collectively, we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity. Its manipulation could be used for the development of vaccines and adjuvants.


Subject(s)
AIDS Vaccines/immunology , B-Cell Activating Factor/immunology , COVID-19 Vaccines/immunology , Cytidine Deaminase/immunology , HIV-1/immunology , Nanoparticles , SARS-CoV-2/immunology , Signal Transduction/immunology , Ubiquitin Thiolesterase/immunology , Ubiquitination/immunology , AIDS Vaccines/genetics , Animals , B-Cell Activating Factor/genetics , COVID-19 Vaccines/genetics , Cytidine Deaminase/genetics , HEK293 Cells , HIV-1/genetics , Humans , Mice , Mice, Knockout , SARS-CoV-2/genetics , Signal Transduction/genetics , Ubiquitin Thiolesterase/genetics
3.
Int J Nanomedicine ; 16: 8141-8158, 2021.
Article in English | MEDLINE | ID: covidwho-1581579

ABSTRACT

Chitosan has been investigated in several biological fields, including drug and gene delivery, tissue engineering antiviral and immunological adjuvant methods. It's a cationic copolymer of N-acetyl glucosamine and D-glucosamine with different molecular chain lengths, compositions, and sequences than N-acetyl glucosamine and D-glucosamine. It is biocompatible and cyto-compatible, as well as recyclable and bioresorbable. As effective drug delivery methods, chitosan nanoparticles are shaped into several pathways. The purpose of this article is to provide an overview of its antiviral application as a nanocarrier for antiviral medications, highlighting the benefits, limitations, and downsides. In this review, we will report the most recent COVID-19 vaccination advances. It will also be discussed what the future holds for chitosan nanoparticles in the treatment of coronaviruses.


Subject(s)
COVID-19 , Chitosan , Nanoparticles , Antiviral Agents , COVID-19/drug therapy , COVID-19 Vaccines , Drug Carriers , Drug Delivery Systems , Humans , SARS-CoV-2
4.
Molecules ; 27(1)2021 Dec 28.
Article in English | MEDLINE | ID: covidwho-1580565

ABSTRACT

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (-36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer-Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations.


Subject(s)
Azetidines/pharmacokinetics , Drug Carriers/chemistry , Drug Liberation , Liposomes/chemistry , Nanoparticles/chemistry , Polymers/chemistry , Purines/pharmacokinetics , Pyrazoles/pharmacokinetics , Sulfonamides/pharmacokinetics , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/chemistry , Biological Availability , Male , Purines/administration & dosage , Purines/chemistry , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Rats , Rats, Wistar , Sulfonamides/administration & dosage , Sulfonamides/chemistry
5.
Methods Mol Biol ; 2410: 111-129, 2022.
Article in English | MEDLINE | ID: covidwho-1575756

ABSTRACT

Infectious diseases are a leading cause of death worldwide, and vaccines are the cheapest and efficient approach to preventing diseases. Use of conventional vaccination strategies such as live, attenuated, and subunit has limitations as it does not fully provide protection against many infectious diseases. Hence, there was a need for the development of a new vaccination strategy. Use of nucleic acids-DNA and RNA-has emerged as promising alternative to conventional vaccine approaches. Knowledge of mRNA biology, chemistry, and delivery systems in recent years have enabled mRNA to become a promising vaccine candidate. One of the advantages of a mRNA vaccine is that clinical batches can be generated after the availability of a sequence encoding the immunogen. The process is cell-free and scalable. mRNA is a noninfectious, nonintegrating molecule and there is no potential risk of infection or mutagenesis. mRNA is degraded by normal cellular processes, and its in vivo half-life can be regulated by different modifications and delivery methods. The efficacy can be increased by modifications of the nucleosides that can make mRNA more stable and highly translatable. Efficient in vivo delivery can be achieved by formulating mRNA into carrier molecules, allowing rapid uptake and expression in the cytoplasm. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The spike (S) glycoprotein mediates host cell attachment and is required for viral entry; it is the primary vaccine target for many candidate SARS-CoV-2 vaccines. Development of a lipid nanoparticle encapsulated mRNA vaccine that encodes the SARS-CoV-2 S glycoprotein stabilized in its prefusion conformation conferred 95% protection against Covid-19.


Subject(s)
Viral Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Liposomes , Nanoparticles , Spike Glycoprotein, Coronavirus , Viral Vaccines/genetics
6.
Int J Mol Sci ; 22(24)2021 Dec 14.
Article in English | MEDLINE | ID: covidwho-1572495

ABSTRACT

The pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has upended healthcare systems and economies around the world. Rapid understanding of the structural biology and pathogenesis of SARS-CoV-2 has allowed the development of emergency use or FDA-approved vaccines and various candidate vaccines. Among the recently developed SARS-CoV-2 candidate vaccines, natural protein-based nanoparticles well suited for multivalent antigen presentation and enhanced immune stimulation to elicit potent humoral and cellular immune responses are currently being investigated. This mini-review presents recent innovations in protein-based nanoparticle vaccines against SARS-CoV-2. The design and strategy of displaying antigenic domains, including spike protein, receptor-binding domain (RBD), and other domains on the surface of various protein-based nanoparticles and the performance of the developed nanoparticle-based vaccines are highlighted. In the final part of this review, we summarize and discuss recent advances in clinical trials and provide an outlook on protein-based nanoparticle vaccines.


Subject(s)
COVID-19 Vaccines/immunology , Nanoparticles/chemistry , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigen Presentation/immunology , COVID-19/immunology , COVID-19 Vaccines/pharmacology , Humans , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Vaccines/immunology
7.
Immunity ; 54(12): 2695-2697, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1568761

ABSTRACT

Adjuvants can be incorporated into vaccines to enhance the magnitude and functionality of adaptive immune responses. In this issue of Immunity, Alameh et al. (2021) reveal that lipid nanoparticles, which are key components of effective SARS-CoV-2 mRNA vaccines, have broad adjuvant function, enhancing B cell responses and protective efficacy of protein-based subunit in addition to mRNA antigens.


Subject(s)
COVID-19 , Adjuvants, Immunologic , Humans , Liposomes , Nanoparticles , SARS-CoV-2
8.
Int J Nanomedicine ; 16: 6575-6591, 2021.
Article in English | MEDLINE | ID: covidwho-1533527

ABSTRACT

Public awareness of infectious diseases has increased in recent months, not only due to the current COVID-19 outbreak but also because of antimicrobial resistance (AMR) being declared a top-10 global health threat by the World Health Organization (WHO) in 2019. These global issues have spiked the realization that new and more efficient methods and approaches are urgently required to efficiently combat and overcome the failures in the diagnosis and therapy of infectious disease. This holds true not only for current diseases, but we should also have enough readiness to fight the unforeseen diseases so as to avoid future pandemics. A paradigm shift is needed, not only in infection treatment, but also diagnostic practices, to overcome the potential failures associated with early diagnosis stages, leading to unnecessary and inefficient treatments, while simultaneously promoting AMR. With the development of nanotechnology, nanomaterials fabricated as multifunctional nano-platforms for antibacterial therapeutics, diagnostics, or both (known as "theranostics") have attracted increasing attention. In the research field of nanomedicine, mesoporous silica nanoparticles (MSN) with a tailored structure, large surface area, high loading capacity, abundant chemical versatility, and acceptable biocompatibility, have shown great potential to integrate the desired functions for diagnosis of bacterial infections. The focus of this review is to present the advances in mesoporous materials in the form of nanoparticles (NPs) or composites that can easily and flexibly accommodate dual or multifunctional capabilities of separation, identification and tracking performed during the diagnosis of infectious diseases together with the inspiring NP designs in diagnosis of bacterial infections.


Subject(s)
Bacterial Infections , COVID-19 , Nanoparticles , Bacterial Infections/diagnosis , Bacterial Infections/drug therapy , Humans , Porosity , SARS-CoV-2 , Silicon Dioxide
9.
Theranostics ; 11(14): 7005-7017, 2021.
Article in English | MEDLINE | ID: covidwho-1524524

ABSTRACT

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Indoles/pharmacology , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Phenothiazines/pharmacology , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/therapeutic use , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Nanoparticles/toxicity , Nanoparticles/ultrastructure , Phenothiazines/chemistry , Phenothiazines/pharmacokinetics , Phenothiazines/therapeutic use , Spectroscopy, Fourier Transform Infrared , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
10.
Sci Rep ; 11(1): 21723, 2021 11 05.
Article in English | MEDLINE | ID: covidwho-1503978

ABSTRACT

Coronavirus with intact infectivity attached to PPE surfaces pose significant threat to the spread of COVID-19. We tested the hypothesis that an electroceutical fabric, generating weak potential difference of 0.5 V, disrupts the infectivity of coronavirus upon contact by destabilizing the electrokinetic properties of the virion. Porcine respiratory coronavirus AR310 particles (105) were placed in direct contact with the fabric for 1 or 5 min. Following one minute of contact, zeta potential of the porcine coronavirus was significantly lowered indicating destabilization of its electrokinetic properties. Size-distribution plot showed appearance of aggregation of the virus. Testing of the cytopathic effects of the virus showed eradication of infectivity as quantitatively assessed by PI-calcein and MTT cell viability tests. This work provides the rationale to consider the studied electroceutical fabric, or other materials with comparable property, as material of choice for the development of PPE in the fight against COVID-19.


Subject(s)
COVID-19/prevention & control , COVID-19/transmission , Electrochemistry/methods , Textiles , Animals , Anti-Infective Agents , Body Fluids , Cell Line , Cell Survival , Fluoresceins , Humans , Hydrogen Peroxide , Kinetics , Nanoparticles , Propidium , SARS-CoV-2 , Swine , Temperature , Tetrazolium Salts , Thiazoles , Virion , Wound Healing
11.
Mater Sci Eng C Mater Biol Appl ; 116: 111260, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1452344

ABSTRACT

Polymeric nanoparticulate systems allow the encapsulation of bio-active substances, giving them protection against external agents and increasing the drug's bioavailability. The use of biocompatible and biodegradable polymers usually guarantees the harmless character of the formulation, and a controlled drug release is also assured. A relatively easy procedure to obtain polymeric formulations of bioactive agents is ionotropic gelation, which allows the synthesis of chitosan (CS) - sodium tri-polyphosphate nanoparticles (NPs) loading encapsulated proteins. In this work, Bovine serum albumin (BSA) model protein and a recombinant porcine alpha interferon variant were used to obtain nanoparticulate formulations. The internalization of the encapsulated material by cells was studied using a BSA-fluorescein system; the fluorescent conjugate was observable inside the cells after 20 h of incubation. The therapeutic CS-alpha interferon formulation showed a maximum of protein released in vitro at around 90 h. This system was found to be safe in a cytotoxicity assay, while biological activity experiments in vitro showed antiviral protection of cells in the presence of encapsulated porcine alpha interferon. In vivo experiments in pigs revealed a significant and sustained antiviral response through overexpression of the antiviral markers OAS2 and PKR. This proves the preservation of porcine alpha interferon biological activity, and also that a lasting response was obtained. This procedure is an effective and safe method to formulate drugs in nanoparticulate systems, representing a significant contribution to the search for more effective drug delivery strategies.


Subject(s)
Chitosan , Nanoparticles , Pharmaceutical Preparations , Animals , Antiviral Agents/pharmacology , Biological Availability , Cattle , Drug Carriers , Drug Delivery Systems , Interferon-alpha , Particle Size , Polymers , Swine
12.
Emerg Microbes Infect ; 10(1): 2016-2029, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1493580

ABSTRACT

ABSTRACTA COVID-19 vaccine that can give early protection is needed to eliminate the viral spread efficiently. Here, we demonstrate the development of a nanoparticle vaccine candidate, REVC-128, in which multiple trimeric spike ectodomains with glycine (G) at position 614 were multimerized onto a nanoparticle. In-vitro characterization of this vaccine confirms its structural and antigenic integrity. In-vivo immunogenicity evaluation in mice indicates that a single dose of this vaccine induces potent serum neutralizing antibody titre at two weeks post-immunization. This is significantly higher than titre caused by trimeric spike protein without nanoparticle presentation. The comparison of serum binding to spike subunits between animals immunized by a spike with and without nanoparticle presentation indicates that nanoparticle prefers the display of spike RBD (Receptor-Binding Domain) over S2 subunit, likely resulting in a more neutralizing but less cross-reactive antibody response. Moreover, a Syrian golden hamster in-vivo model for the SARS-CoV-2 virus challenge was implemented two weeks post a single dose of REVC-128 immunization. The results showed that vaccination protects hamsters against the SARS-CoV-2 virus challenge with evidence of steady body weight, suppressed viral loads and alleviation of tissue damage for protected animals, compared with ∼10% weight loss, high viral loads and tissue damage in unprotected animals. Furthermore, the data showed that vaccine REVC-128 is thermostable at up to 37°C for at least 4 weeks. These findings, along with a history of safety for protein vaccines, suggest that the REVC-128 is a safe, stable and efficacious single-shot vaccine to give the earliest protection against SARS-CoV-2 infection.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/chemistry , SARS-CoV-2 , Animals , Antibodies, Neutralizing , Antibodies, Viral/blood , Antibody Formation , COVID-19 Vaccines/administration & dosage , Cricetinae , Humans , Immunization , Immunization Schedule , Immunogenicity, Vaccine , Mesocricetus , Mice , Spike Glycoprotein, Coronavirus , Vaccination , Viral Load
13.
Sci Rep ; 11(1): 21308, 2021 10 29.
Article in English | MEDLINE | ID: covidwho-1493219

ABSTRACT

The aim of this study was to present and evaluate novel oral vaccines, based on self-amplifying RNA lipid nanparticles (saRNA LNPs), saRNA transfected Lactobacillus plantarum LNPs, and saRNA transfected Lactobacillus plantarum, to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) variants alpha and delta. After invitro evaluation of the oral vaccines on HEK293T/17 cells, we found that saRNA LNPs, saRNA transfected Lactobacillus plantarum LNPs, and saRNA transfected Lactobacillus plantarum could express S-protein at both mRNA and protein levels. In the next step, BALB/c mice were orally vaccinated with saRNA LNPs, saRNA transfected Lactobacillus plantarum LNPs, and saRNA transfected Lactobacillus plantarum at weeks 1 and 3. Importantly, a high titer of IgG and IgA was observed by all of them, sharply in week 6 (P < 0.05). In all study groups, their ratio of IgG2a/IgG1 was upper 1, indicating Th1-biased responses. Wild-type viral neutralization assay showed that the secreted antibodies in vaccinated mice and recovered COVID-19 patients could neutralize SARS-COV-2 variants alpha and delta. After oral administration of oral vaccines, biodistribution assay was done. It was found that all of them had the same biodistribution pattern. The highest concentration of S-protein was seen in the small intestine, followed by the large intestine and liver.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Lactobacillus plantarum/genetics , Lipids/chemistry , Nanoparticles/chemistry , SARS-CoV-2/immunology , Transfection/methods , Vaccination/methods , Vaccines, Synthetic/administration & dosage , Administration, Oral , Adult , Animals , COVID-19/blood , COVID-19/virology , COVID-19 Vaccines/pharmacokinetics , Female , HEK293 Cells , Humans , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Intestine, Small/metabolism , Lactobacillus plantarum/metabolism , Male , Mice , Mice, Inbred BALB C , Middle Aged , Models, Animal , Neutralization Tests , RNA, Messenger/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Tissue Distribution
14.
J Am Chem Soc ; 143(43): 17975-17982, 2021 11 03.
Article in English | MEDLINE | ID: covidwho-1483092

ABSTRACT

Targeted and efficient delivery of nucleic acids with viral and synthetic vectors is the key step of genetic nanomedicine. The four-component lipid nanoparticle synthetic delivery systems consisting of ionizable lipids, phospholipids, cholesterol, and a PEG-conjugated lipid, assembled by microfluidic or T-tube technology, have been extraordinarily successful for delivery of mRNA to provide Covid-19 vaccines. Recently, we reported a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) synthetic delivery system for mRNA relying on amphiphilic Janus dendrimers and glycodendrimers developed in our laboratory. Amphiphilic Janus dendrimers consist of functional hydrophilic dendrons conjugated to hydrophobic dendrons. Co-assembly of IAJDs with mRNA into dendrimersome nanoparticles (DNPs) occurs by simple injection in acetate buffer, rather than by microfluidic devices, and provides a very efficient system for delivery of mRNA to lung. Here we report the replacement of most of the hydrophilic fragment of the dendron from IAJDs, maintaining only its ionizable amine, while changing its interconnecting group to the hydrophobic dendron from amide to ester. The resulting IAJDs demonstrated that protonated ionizable amines play dual roles of hydrophilic fragment and binding ligand for mRNA, changing delivery from lung to spleen and/or liver. Replacing the interconnecting ester with the amide switched the delivery back to lung. Delivery predominantly to liver is favored by pairs of odd and even alkyl groups in the hydrophobic dendron. This simple structural change transformed the targeted delivery of mRNA mediated with IAJDs, from lung to liver and spleen, and expands the utility of DNPs from therapeutics to vaccines.


Subject(s)
Dendrimers/chemistry , RNA, Messenger/chemistry , Amines/chemistry , Animals , Esters/chemistry , Hydrophobic and Hydrophilic Interactions , Ions/chemistry , Mice , Nanoparticles/chemistry , RNA, Messenger/immunology , RNA, Messenger/metabolism , Vaccines, Synthetic/chemistry , Vaccines, Synthetic/immunology , Vaccines, Synthetic/metabolism
15.
J Am Chem Soc ; 143(43): 17891-17909, 2021 11 03.
Article in English | MEDLINE | ID: covidwho-1483091

ABSTRACT

The emergence of multi-drug-resistant pathogens threatens the healthcare systems world-wide. Recent advances in phototherapy (PT) approaches mediated by photo-antimicrobials (PAMs) provide new opportunities for the current serious antibiotic resistance. During the PT treatment, reactive oxygen species or heat produced by PAMs would react with the cell membrane, consequently leaking cytoplasm components and effectively eradicating different pathogens like bacteria, fungi, viruses, and even parasites. This Perspective will concentrate on the development of different organic photo-antimicrobials (OPAMs) and their application as practical therapeutic agents into therapy for local infections, wound dressings, and removal of biofilms from medical devices. We also discuss how to design highly efficient OPAMs by modifying the chemical structure or conjugating with a targeting component. Moreover, this Perspective provides a discussion of the general challenges and direction for OPAMs and what further needs to be done. It is hoped that through this overview, OPAMs can prosper and will be more widely used for microbial infections in the future, especially at a time when the global COVID-19 epidemic is getting more serious.


Subject(s)
Anti-Infective Agents/chemistry , Drug Design , Phototherapy/methods , Animals , Anti-Infective Agents/pharmacology , Anti-Infective Agents/therapeutic use , Bacteria/drug effects , Biofilms/drug effects , Biofilms/radiation effects , Coloring Agents/chemistry , Coloring Agents/pharmacology , Equipment and Supplies/microbiology , Equipment and Supplies/virology , Escherichia coli/drug effects , Escherichia coli/physiology , Eye Diseases/drug therapy , Eye Diseases/pathology , Fungi/drug effects , Graphite/chemistry , Light , Nanoparticles/chemistry , Nanoparticles/toxicity , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Quantum Theory , Reactive Oxygen Species/metabolism , Viruses/drug effects
16.
ACS Infect Dis ; 7(11): 3096-3110, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1483084

ABSTRACT

The development of vaccines against coronaviruses has focused on the spike (S) protein, which is required for the recognition of host-cell receptors and thus elicits neutralizing antibodies. Targeting conserved epitopes on the S protein offers the potential for pan-beta-coronavirus vaccines that could prevent future pandemics. We displayed five B-cell epitopes, originally identified in the convalescent sera from recovered severe acute respiratory syndrome (SARS) patients, on the surface of the cowpea mosaic virus (CPMV) and evaluated these formulations as vaccines. Prime-boost immunization of mice with three of these candidate vaccines, CPMV-988, CPMV-1173, and CPMV-1209, elicited high antibody titers that neutralized the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro and showed an early Th1-biased profile (2-4 weeks) transitioning to a slightly Th2-biased profile just after the second boost (6 weeks). A pentavalent slow-release implant comprising all five peptides displayed on the CPMV elicited anti-S protein and epitope-specific antibody titers, albeit at a lower magnitude compared to the soluble formulations. While the CPMV remained intact when released from the PLGA implants, processing results in loss of RNA, which acts as an adjuvant. Loss of RNA may be a reason for the lower efficacy of the implants. Finally, although the three epitopes (988, 1173, and 1209) that were found to be neutralizing the SARS-CoV were 100% identical to the SARS-CoV-2, none of the vaccine candidates neutralized the SARS-CoV-2 in vitro suggesting differences in the natural epitope perhaps caused by conformational changes or the presence of N-linked glycans. While a cross-protective vaccine candidate was not developed, a multivalent SARS vaccine was developed. The technology discussed here is a versatile vaccination platform that can be pivoted toward other diseases and applications that are not limited to infectious diseases.


Subject(s)
COVID-19 , Comovirus , Nanoparticles , Vaccines , Animals , COVID-19/therapy , Comovirus/genetics , Epitopes, B-Lymphocyte , Humans , Immunization, Passive , Mice , Peptides , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
17.
Phytother Res ; 35(10): 5527-5563, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1479440

ABSTRACT

Today, due to the prevalence of various diseases such as the novel coronavirus (SARS-CoV-2), diabetes, central nervous system diseases, cancer, cardiovascular disorders, and so on, extensive studies have been conducted on therapeutic properties of natural and synthetic agents. A literature review on herbal medicine and commercial products in the global market showed that curcumin (Cur) has many therapeutic benefits compared to other natural ingredients. Despite the unique properties of Cur, its use in clinical trials is very limited. The poor biopharmaceutical properties of Cur such as short half-life in plasma, low bioavailability, poor absorption, rapid metabolism, very low solubility (at acidic and physiological pH), and the chemical instability in body fluids are major concerns associated with the clinical applications of Cur. Recently, nanoformulations are emerging as approaches to develop and improve the therapeutic efficacy of various drugs. Many studies have shown that Cur nanoformulations have tremendous therapeutic potential against various diseases such as SARS-CoV-2, cancer, inflammatory, osteoporosis, and so on. These nanoformulations can inhibit many diseases through several cellular and molecular mechanisms. However, successful long-term clinical results are required to confirm their safety and clinical efficacy. The present review aims to update and explain the therapeutic potential of Cur nanoformulations.


Subject(s)
COVID-19 , Curcumin , Nanoparticles , Neoplasms , Biological Availability , Humans , SARS-CoV-2
18.
Acc Chem Res ; 54(21): 4001-4011, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1475239

ABSTRACT

Since the U.S. Food and Drug Administration (FDA) granted emergency use authorization for two mRNA vaccines against SARS-CoV-2, mRNA-based technology has attracted broad attention from the scientific community to investors. When delivered intracellularly, mRNA has the ability to produce various therapeutic proteins, enabling the treatment of a variety of illnesses, including but not limited to infectious diseases, cancers, and genetic diseases. Accordingly, mRNA holds significant therapeutic potential and provides a promising means to target historically hard-to-treat diseases. Current clinical efforts harnessing mRNA-based technology are focused on vaccination, cancer immunotherapy, protein replacement therapy, and genome editing. The clinical translation of mRNA-based technology has been made possible by leveraging nanoparticle delivery methods. However, the application of mRNA for therapeutic purposes is still challenged by the need for specific, efficient, and safe delivery systems.This Account highlights key advances in designing and developing combinatorial synthetic lipid nanoparticles (LNPs) with distinct chemical structures and properties for in vitro and in vivo intracellular mRNA delivery. LNPs represent the most advanced nonviral nanoparticle delivery systems that have been extensively investigated for nucleic acid delivery. The aforementioned COVID-19 mRNA vaccines and one LNP-based small interfering RNA (siRNA) drug (ONPATTRO) have received clinical approval from the FDA, highlighting the success of synthetic ionizable lipids for in vivo nucleic acid delivery. In this Account, we first summarize the research efforts from our group on the development of bioreducible and biodegradable LNPs by leveraging the combinatorial chemistry strategy, such as the Michael addition reaction, which allows us to easily generate a large set of lipidoids with diverse chemical structures. Next, we discuss the utilization of a library screening strategy to identify optimal LNPs for targeted mRNA delivery and showcase the applications of the optimized LNPs in cell engineering and genome editing. Finally, we outline key challenges to the clinical translation of mRNA-based therapies and propose an outlook for future directions of the chemical design and optimization of LNPs to improve the safety and specificity of mRNA drugs. We hope this Account provides insight into the rational design of LNPs for facilitating the development of mRNA therapeutics, a transformative technology that promises to revolutionize future medicine.


Subject(s)
COVID-19 Vaccines/pharmacology , Gene Editing , Gene Transfer Techniques , Lipids/chemistry , Nanoparticles/chemistry , RNA, Messenger/pharmacology , COVID-19/drug therapy , COVID-19 Vaccines/chemistry , Genetic Therapy , Humans , RNA, Messenger/chemistry , SARS-CoV-2/drug effects
19.
Eur Heart J ; 42(6): 555-557, 2021 02 11.
Article in English | MEDLINE | ID: covidwho-1472264

Subject(s)
Nanoparticles , Humans
20.
Nucleic Acid Ther ; 31(5): 321-323, 2021 10.
Article in English | MEDLINE | ID: covidwho-1467290

ABSTRACT

The utilization of the mRNA-based Pfizer-BioNTech and Moderna coronavirus disease 2019 (COVID-19) vaccines represents the culmination of many years of nonviral nucleic acid delivery, but more importantly, they signify a massive clinical scientific success. Scientists working in the area of nucleic acid delivery using lipid nanoparticles will undoubtedly be energized by the success of these vaccines and begin to collect much needed data in the realm of nonviral-based RNA and DNA delivery, specifically, the use of lipid nanoparticles, the immune response, safety, and efficacy. It is easily conceivable that in the future we can utilize these data to help streamline our approach for the delivery of DNA for gene therapy and regulatory RNAs for therapeutic and regenerative medicine (ie, wound repair) applications.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , DNA/pharmacokinetics , Gene Transfer Techniques , RNA, Messenger/pharmacokinetics , Biotechnology/trends , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/biosynthesis , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , DNA/chemistry , Data Mining , Dependovirus/genetics , Dependovirus/immunology , Humans , Liposomes/chemistry , Liposomes/pharmacokinetics , Nanoparticles/administration & dosage , Nanoparticles/chemistry , RNA, Messenger/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
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