PMC:7299399 / 2339-11388 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7299399","sourcedb":"PMC","sourceid":"7299399","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7299399","text":"COVID-19: Setting the Scene for Nanotechnology\nThrough millions of years of evolution, viruses have gained a variety of molecular mechanisms for entry into cells; long-term survival within cells; and activation, inhibition, or modification of the host defense mechanisms at all levels.1 Their ability to transfer genes with high efficiency inspired the development of noninfectious recombinant viral vectors for gene-therapy applications, beginning in 1990.2−4 Efforts were then underway to improve the safety of viral vectors, including developing nonviral drug-delivery systems inspired by the natural capabilities of viruses. Researchers in the field of nanomedicine have designed a variety of nanosystems that can mimic the gene-transfer capacity and high infectivity of viral vectors. By learning the molecular mechanisms behind these vectors, nanomedicine and biomedical researchers have developed delivery systems used in different fields, including cancer therapy and regenerative medicine.5,6 However, nanotechnology is not only inspired by virology to develop novel delivery tools but also at the forefront in combatting dangerous viruses.\nViral infections are one of the leading causes of morbidity and mortality worldwide and one of the main reasons for significant economic losses.7−9 Standard treatment approaches mainly rely on vaccination and therapeutics derived through targeting key processes in the virus life cycle. However, many viruses evolve subject to selective pressures, often becoming drug resistant, which necessitates additional resources for the development of new drugs.\nA novel coronavirus causing pneumonia was identified in China in December 2019. On February 11, the Coronavirus Study Group (CGS) of the International Committee on Virus Taxonomy (ICTV) designated the virus as SARS-CoV-2 based on phylogeny and taxonomy.10 The same day, the Director General of the World Health Organization (WHO) designated the disease caused by SARS-CoV-2 “coronavirus disease 2019” (COVID-19). On March 11, 2020, the WHO declared the COVID-19 outbreak a pandemic. As of May 2020, SARS-CoV-2 has spread across the world in over 185 countries, with millions of infections and hundreds of thousands of deaths.11\nThe main symptoms of COVID-19 are fever (85.6%), cough (68.7%), and fatigue (39.4%). Other less common symptoms include dyspnea, headache, loss of appetite, panting, sore throat, vomiting, diarrhea, rhinorrhea, and abdominal pain. The severity of disease in patients depends mainly on the presence of comorbidities such as hypertension, diabetes, and coronary heart disease.12,13 The incubation period is reported to be between 5 and 14 days before disease onset.14 Recent reports indicate that some COVID-19 patients exhibit damage in other organs such as the heart, kidney, eye (conjunctivitis), and brain (encephalitis).15−18 The race is on to develop drugs and treatment options to combat COVID-19, harnessing all of the tools and technologies modern molecular medicine can offer.\nThe genome of SARS-CoV-2 has been fully sequenced19 and shows a high degree of similarity in key genes with other coronaviruses causing respiratory diseases such as SARS-CoV.20 Based on knowledge gathered during the SARS-CoV epidemic, a key target of the virus includes the surface receptor in human cells, angiotensin-converting enzyme II (ACE2), which is required for efficient uptake in host cells.19,21−23\nThe C-terminal domain (i.e., receptor-binding domain of the envelope-embedded spike (S) 1 protein) of SARS-CoV-2 binds ACE2. The molecular details of this interaction have been provided by solving the crystal structure of the complex.24 Because binding of the S protein to ACE2 is critical for the first steps of infection, the most common treatment approaches focus on disrupting this key event. At present, there are three main strategies to block ACE2 binding: (i) administration of soluble, recombinant ACE2 protein, which acts as a decoy receptor to scavenge the virus and, thus, to prevent uptake into host cells;21 (ii) vaccination with antibodies that specifically bind to the S protein and interfere with ACE2 interaction; and (iii) inhibition of host proteases that process the S protein and are essential for ACE2 binding and subsequent membrane fusion to enable intracellular delivery of the virus.23\nAs shown in Figure 1, the first events of the infection (i.e., the interactions of the virus with the target cells expressing ACE2) are in the process of being elucidated at the molecular level. However, as patients suffering from severe symptoms—which usually develop only after several days or a week—already bear a high viral load in the lungs, there is a pressing need for strategies not only to prevent infection of the host cells but also to attack pre-existing persistent viruses and to prevent life-threatening processes, such as hyperinflammation in the lung and multiple-organ failure.25 Notably, a comprehensive protein–protein interaction (PPI) map of most viral proteins with the human proteome has been established to provide potentially novel targets for treatment employing already U.S. Food and Drug Administration (FDA)-approved drugs via a process known as drug repurposing.26\nFigure 1 SARS-CoV-2 viral life cycle and potential targets for nanomaterials. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors on the host cell surface. Transmembrane serine protease 2 (TMPRSS2) facilitates cellular entry through protease activity. Later, viral particles are internalized and enter into endosomes. Due to the low pH of endosomes, viral particles are uncoated and the viral genome is released for protein synthesis. Following viral RNA and protein synthesis, new infectious particles are assembled and released. The development process of antiviral therapies typically requires years before the therapies can be made widely available27 because there are a number of regulatory steps required to establish the safety and efficacy of vaccines and drugs.28 Moreover, the highly specific viral targets might change as SARS-CoV-2 continues to mutate, resulting in resistance to medication, such as has been observed when attempting to treat other viral infections. Overviews of the identification of candidate drugs for SARS-CoV-2 are detailed in refs (29−31).\nIn the past decade, there has been growing interest in novel, broad-spectrum antiviral compounds, which might be less prone to resistance and could be employed against a wide class of different viruses, including new variants.32−34 Importantly, such therapies could be prescribed until more sophisticated, targeted drugs and vaccines are available for each new emerging virus.\nNanotechnology offers a number of solutions to fight viruses, both outside and inside the host, and several nanotechnology-based platforms have already been successful in preclinical studies to counter several human viral pathogens such as HIV, human papilloma virus, herpes simplex, and respiratory viruses.32−35 Nanotechnology-based approaches should be leveraged to help the fight against COVID-19 as well as any future pandemics, in a number of ways, including (i) novel vaccines and drugs, where nanomaterials can be leveraged for direct delivery of broad-spectrum antivirals and to support targeted therapies to the lungs; (ii) highly specific, rapid, and sensitive tests to detect infection or to detect immunity (serological tests); (iii) superfine filters for face masks or blood filtering; (iv) novel surfaces or surface coatings that are resistant to viral adhesion and can inactivate the virus; and (v) the improvement of tools for contact tracing (Figure 2).\nFigure 2 Nanomaterials for prevention and therapy of COVID-19. Integrating nanomaterials into personal protective equipment (PPE) can prevent the entrance of SARS-CoV-2 in the respiratory system. Nanomaterials could also be used to deliver drugs to the pulmonary system via inhalators. Cellular binding of viral particles at the alveoli can be inhibited using targeted nanoparticles (NPs) against angiotensin-converting enzyme 2 (ACE2) receptors or viral S protein. Various mechanisms can be used to inactivate viral particles systemically such as using neutralizing NPs or photocatalytic nanomaterials. Nanomaterial-based vaccines or immunomodulation can be used to prevent SARS-CoV-2 infection or even to boost the immune response during infection. PDT, photodynamic therapy. This crisis has also highlighted the importance of rapid prototyping/manufacturing for addressing unforeseen needs, such as in case of a pandemic, where large-scale production of equipment including ventilators and personal protective equipment (PPE) is urgently needed and nanotechnology may aid (e.g., in providing readily synthesizable materials for equipment manufacturing as well as for the improvement of their efficiency and durability). In the next sections, we expand and elaborate on the specific contributions that nanotechnology can offer to counter COVID-19 and similar 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