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A large scale of pandemic coronavirus disease (COVID-19) in the past five years motivates a great deal of endeavors donating to the exploration on therapeutic drugs against COVID-19 as well as other diseases caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein is an overview on the organic small molecules that are potentially employed to treat COVID-19 and other SARS-CoV-2-related diseases. These organic small molecules are accessed from both natural resources and synthetic strategies. Notably, typical natural products presented herein consist of polyphenols, lignans, alkaloids, terpenoids, and peptides, which exert an advantage for the further discovery of novel anti-COVID-19 drugs from plant herbs. On the other hand, synthetic prodrugs are composed of a series of inhibitors towards RNA-dependent RNA polymerase (RdRp), main protease (Mpro), 3-chymotrypsin-like cysteine protease (3CLpro), spike protein, papain-like protease (PLpro) of the SARS-CoV-2 as well as the angiotensin-converting enzyme 2 (ACE2) in the host cells. Synthetic strategies are worth taken into consideration because they are beneficial for designing novel anti-COVID-19 drugs in the coming investigations. Although examples collected herein are just a drop in the bucket, developments of organic small molecules against coronavirus infections are believed to pave a promising way for the discovery of multi-targeted therapeutic drugs against not only COVID-19 but also other virus-mediated diseases.

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Mixed ligand complexes of manganese(II), cobalt(II), copper(II), and cadmium(II)with an innovative Schiff base ligand denoted as (L1), 4-(2-((1E,2E)-1-(2-(p-tolyl)hydrazineylidene)propan-2-ylidene)hydrazineyl), served as the principal ligand, while glycine (L2) was employed as secondary ligand were successfully effectively characterized through a comprehensive set of analyses, including Elemental analysis, UV-Visible, FT-IR, Mass spectra, and conductometric measurements. Density functional theory (DFT) computations were executed to discern the enduring electronic arrangement, the energy gap, dipole moment and chemical hardness of the hybrid ligand assemblies. The proposed geometry for the complexes is a distorted octahedral structure. The antimicrobial efficacy of these compounds was assessed against a range of bacterial and fungal strains. Notably, these complexes exhibited promising antimicrobial activities, with the cadmium (II) complex demonstrating superior efficacy towards all tested organisms. These compounds were also examined for their antibiotic properties against H. pylori to explore their broader medical potential. The Schiff base ligand and its corresponding metal complexes displayed substantial potential as an antibiotic against H. pylori. Additionally, the antitumor potential of the synthesized complexes was assessed against MCF-7 (Breast carcinoma) cells-the Cu (II) complex demonstrated superior activity with the lowest IC50 value compared to cisplatin. Moreover, it exhibited reduced cytotoxicity towards normal cells (VERO cells) compared to cisplatin, establishing it as the most potent compound in the study. Furthermore, molecular docking was explored of the Schiff base ligand and its corresponding cadmium(II) complex. The analysis of the docking study yielded valuable structural insights that can be effectively utilized in conducting inhibition studies for example against COVID-19. This comprehensive study highlights these synthesized compounds' multifaceted applications and promising bioactive properties.

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Corona Virus Disease 19 (COVID-19) has been a major pandemic impacting a huge population worldwide, and it continues to present serious health threats, necessitating the development of novel protective nutraceuticals. Biobran/MGN-3, an arabinoxylan rice bran, is a potent immunomodulator for both humans and animals that has recently been demonstrated to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We here investigate Biobran/MGN-3's potential to enhance an antiviral immune response in humans. Peripheral blood mononuclear cells (PBMCs) derived from eight subjects taking Biobran/MGN-3 (age 55-65 years) and eight age-matched control subjects were stimulated with irradiated SARS-CoV-2 virus and then subjected to immuno-phenotyping and multiplex cytokine/chemokine assays. Results showed that PBMCs from subjects supplemented with Biobran/MGN-3 had significantly increased activation of plasmacytoid dendritic cells (pDCs) coupled with increased IFN-α secretion. We also observed higher baseline expression of HLA-DR (human leukocyte antigen-DR isotype) on dendritic cells (DCs) and increased secretion of chemokines and cytokines, as well as a substantial increase in cytotoxic T cell generation for subjects taking Biobran/MGN-3. Our results suggest that Biobran/MGN-3 primes immunity and therefore may be used for boosting immune responses against SARS-CoV-2 infections and other diseases, particularly in high-risk populations such as the elderly.

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BACKGROUND: Healthcare-associated infections (HAIs) burden healthcare globally. Amid the SARS-CoV-2 pandemic, intensified infection control measures, such as mask usage and hand hygiene, were implemented. AIM: To assess the efficacy of these measures in preventing HAIs among hospitalized patients. METHODS: Using the PICO framework (Population, Intervention, Comparison, Outcome), the study focused on hospitalized patients and the effectiveness of anti-COVID-19 measures in preventing HAIs. A systematic review of literature published in 2020-2022 was conducted, examining interventions such as mask usage, hand hygiene, and environmental cleaning. FINDINGS: This systematic review analysed 42 studies: two in 2020, 21 in 2021, and 19 in 2022. Most studies were from high-income countries (28). Most studies (30 out of 42) reported a reduction in HAIs after implementing anti-COVID-19 measures. Gastrointestinal infections and respiratory tract infections showed significant reduction, unlike bloodstream infections and urinary tract infections. Some wards, like cardiology and neurology, experienced reduced HAIs, unlike intensive care units and coronary care units. There was an increase in studies reporting no effect of hygiene measures on HAIs in 2022, eventually indicating a shift in effectiveness over time. CONCLUSION: Anti-COVID-19 measures have shown selective efficacy in preventing HAIs. The study emphasizes the need for context-specific strategies and increased focus on regions with limited resources. Continued research is essential to refine infection control practices, especially in high-risk settings.

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In response to Chen et al.'s comments on our paper regarding the significance of anti-COVID-IgA antibody response in COVID-19 breakthrough infection in vaccinated patients, we have highlighted the role and the scope of this paper in this correspondence. The role of anti-COVID-19-IgA is already known. The objective of the previous study was to see its role in breakthrough-infected patients. To analyse this effect, we recruited patients with COVID-19 infection after they were fully vaccinated and compared them with the vaccinated group who did not get the infection. Both groups were equally exposed to the virus as all of them were health care workers. We also showed that the anti-COVID-19-NP-IgA was absent in the healthy cohort of our study groups, signifying the absence of natural infection in them during this period. The article also highlights the importance of vaccinating all individuals including those who are immunosuppressed, as it prevents severe COVID-19 infection in these individuals. The physicians should be aware of the fact that immunosuppressed patients are more likely to get COVID-19 breakthrough infection. However, proper vaccination with booster doses prevents severe infection in them.

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new coronavirus in the Coronaviridae family. The COVID-19 pandemic, caused by SARS-CoV-2, has undoubtedly been the largest crisis of the twenty-first century, resulting in over 6.8 million deaths and 686 million confirmed cases, creating a global public health issue. Hundreds of notable articles have been published since the onset of this pandemic to justify the cause of viral spread, viable preventive measures, and future therapeutic approaches. As a result, this review was developed to provide a summary of the current anti-COVID-19 drugs, as well as their timeline, molecular mode of action, and efficacy. It also sheds light on potential future treatment options. Several medications, notably hydroxychloroquine and lopinavir/ritonavir, were initially claimed to be effective in the treatment of SARS-CoV-2 but eventually demonstrated inadequate activity, and the Food and Drug Administration (FDA) withdrew hydroxychloroquine. Clinical trials and investigations, on the other hand, have demonstrated the efficacy of remdesivir, convalescent plasma, and monoclonal antibodies, 6-Thioguanine, hepatitis C protease inhibitors, and molnupiravir. Other therapeutics, including inhaled medicines, flavonoids, and aptamers, could pave the way for the creation of novel anti-COVID-19 therapies. As future pandemics are unavoidable, this article urges immediate action and extensive research efforts to develop potent specialized anti-COVID-19 medications.

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AIM: To evaluate the response (titers of anti-COVID-19 antibodies) to COVID-19 mRNA vaccine of patients with Hashimoto's thyroiditis and normal individuals. PATIENTS AND METHODS: Twenty-four patients with Hashimoto's thyroiditis and 51 normal individuals were studied after the third dose of the vaccine. RESULTS: Patients with Hashimoto's thyroiditis showed significantly higher immune response after the third dose of the COVID-19 mRNA vaccine compared with normal individuals (p = 0.020). After elimination of the four smokers with Hashimoto's thyroiditis, the immune response between the remaining 20 non-smoking patients compared with the response of the 23 non-smoking normal individuals was not different (p = 0.564). There was a significant positive correlation of the anti-COVID-19 antibodies with BMI (p = 0.029) but not with waist circumference in the patients with Hashimoto's thyroiditis (p = 0.054). Similar correlations were not found in normal individuals. Waist circumference could be considered as representative of visceral adipose tissue. In obese normal individuals (BMI ≥ 30), anti-COVID-19 antibodies were not different from those in lean normal individuals (BMI < 25). In obese patients with Hashimoto's thyroiditis, anti-COVID-19 antibodies were significantly higher compared to those in lean patients (p = 0.013). Median anti-COVID-19 antibody titer in obese patients with Hashimoto's thyroiditis was also significantly higher compared to that in obese normal individuals (p = 0.009). CONCLUSIONS: Patients with Hashimoto's thyroiditis show significantly higher immune response after the third dose of the COVID-19 mRNA vaccine compared with normal individuals. Obese patients with Hashimoto's thyroiditis show additionally a significantly higher immune response compared with lean patients.

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Although there is scientific evidence for an increased prevalence of sleep disorders during the coronavirus disease 2019 (COVID-19) pandemic, there is still limited information on how lifestyle factors might have affected sleep patterns. Therefore, we followed a large cohort of participants in the Netherlands (n = 5,420) for up to 1 year (September 2020-2021) via monthly Web-based questionnaires to identify lifestyle changes (physical activity, cigarette smoking, alcohol consumption, electronic device use, and social media use) driven by anti-COVID-19 measures and their potential associations with self-reported sleep (latency, duration, and quality). We used the Containment and Health Index (CHI) to assess the stringency of anti-COVID-19 measures and analyzed associations through multilevel ordinal response models. We found that more stringent anti-COVID-19 measures were associated with higher use of electronic devices (per interquartile-range increase in CHI, odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.40, 1.53), less physical activity (OR = 0.94, 95% CI: 0.90, 0.98), lower frequency of alcohol consumption (OR = 0.63, 95% CI: 0.60, 0.66), and longer sleep duration (OR = 1.11, 95% CI: 1.05, 1.16). Lower alcohol consumption frequency and higher use of electronic devices and social media were associated with longer sleep latency. Lower physical activity levels and higher social media and electronic device use were related to poorer sleep quality and shorter sleep duration.

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AIM: The purpose of the present study was to determine cancer patients' attitudes toward the anti-COVID-19 vaccine. BACKGROUND: Historically, the scientific community's responsibility was to investigate attitudes about vaccination. The course of COVID-19 in cancer patients makes them a high priority for vaccination. Cancer patients are at greater risk of serious complications and death because of COVID-19 infection. OBJECTIVE: The purpose of the present study was to determine cancer patients' attitudes toward the anti-COVID-19 vaccine. We examined several constructs that potentially influenced cancer patients' perceptions of the vaccine: health status, knowledge of COVID-19 and vaccination, cancer patients' perceptions of vulnerability, and attitudes toward general vaccines. METHODS: We conducted a collective case study with 200 cancer patients undergoing treatment, and divided the sample into two groups: patients who "expected to heal" (Group A) and patients who "expected to chronicize" (Group B). Data were collected through a purpose-built questionnaire consisting of 22 questions and a study of medical records. RESULTS: Data analysis showed that both groups, Group A (M= 3.89 SD= 0.64) and Group B (M= 3.98 SD= 0.64), had a favorable attitude toward the anti-COVID-19 vaccine. This favorable attitude toward the anti-COVID-19 vaccine depended on several factors: perception of vulnerability to COVID-19, perception of the severity of their oncological situation, and communication with oncologists. CONCLUSION: Our study highlighted the plurality of factors that influence attitudes toward the anti-COVID-19 vaccine. It is theref+ore of fundamental importance to increase the use of the shared decision-making approach (SDM) to guide the patient to an informed choice.

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During the COVID-19 (coronavirus disease 2019) outbreak, many people were infected, and the symptoms may persist for several weeks or months for recovering patients. This is also known as "long COVID" and includes symptoms such as fatigue, joint pain, muscle pain, et cetera. The COVID-19 virus may trigger hyper-inflammation associated with cytokine levels in the body. COVID-19 can trigger inflammation in the joints, which can lead to osteoarthritis (OA), while long-term COVID-19 symptoms may lead to joint damage and other inflammation problems. According to several studies, sesame has potent anti-inflammatory properties due to its major constituent, sesamin. This study examined sesamin's anti-inflammatory, anti-osteoarthritis, and anti-COVID-19 effects. Moreover, in vivo and in vitro assays were used to determine sesamin's anti-inflammatory activity against the RAW264.7 and SW1353 cell lines. Sesamin had a dose-dependent effect (20 mg/kg) in a monoiodoacetic acid (MIA)-induced osteoarthritis rat model. Sesamin reduced paw swelling and joint discomfort. In addition, the findings indicated that sesamin suppressed the expression of iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) in the RAW264.7 cell line within the concentration range of 6.25-50 µM. Furthermore, sesamin also had a suppressive effect on MMP (matrix metalloproteinase) expression in chondrocytes and the SW1353 cell line within the same concentration range of 6.25-50 µM. To examine the anti-viral activity, an in silico analysis was performed to evaluate sesamin's binding affinity with SARS-CoV-2 RdRp (severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase) and human ACE2 (angiotensin-converting enzyme 2). Compared to the controls, sesamin exhibited strong binding affinities towards SARS-CoV-2 RdRp and human ACE2. Furthermore, sesamin had a higher binding affinity for the ACE2 target protein. This study suggests that sesamin shows potential anti-SARS-CoV-2 activity for drug development.

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Worldwide, the novel coronavirus disease 2019 (COVID-19) has become a significant threat to global health. Worldwide, COVID-19 has affected the health service also in Slovenia. During this time, neurosurgery is facing difficulties in its service, both in emergency and elective surgeries. In the article, we describe the anti-COVID-19 measures taken at our neurosurgical department in a medical centre in Ljubljana, Slovenia, and analysed and compared the number of emergency and elective neurosurgical procedures during the time of the pandemic.

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Patients treated with hemodialysis are often immunocompromised due to concomitant disease. As a result, this population is at high risk of infection and mortality from COVID-19. In addition to symptomatic treatment, a series of antiviral drugs targeting COVID-19 are now emerging. However, these antivirals are used mainly in mild or moderate patients with high-risk factors for progression to severe disease and are not available as pre- or post-exposure prophylaxis for COVID-19. There is a lack of clinical data on the use of anti-COVID-19 drugs, especially in patients treated with hemodialysis, therefore, vaccination remains the main measure to prevent SARS-CoV-2 infection in these patients. Here, we review the clinical features and prognosis of patients on hemodialysis infected with SARS-CoV-2, the main anti-COVID-19 drugs currently available for clinical use, and the safety and efficacy of anti-COVID-19 drugs or COVID-19 vaccination in patients treated with hemodialysis. This information will provide a reference for the treatment and vaccination of COVID-19 in patients treated with hemodialysis and maximize the health benefits of these patients during the outbreak.

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Mexico's pandemic management and the absence of measures have been harshly criticized as being disproportionate. This paper examines whether the proportionality principle was properly applied to Mexico's COVID-19 response and outlines three reasons against such an endeavor, namely (i) the content of "proportionate measures" remained insufficiently well defined, (ii) there were yet fundamental rights conflicts to resolve, and (iii) the situation was moreover characterized by epistemic uncertainty.

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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly infectious positive RNA virus, has spread from its epicenter to other countries with increased mortality and morbidity. Its expansion has hampered humankind's social, economic, and health realms to a large extent. Globally, investigations are underway to understand the complex pathophysiology of coronavirus disease (COVID-19) induced by SARS-CoV-2. Though numerous therapeutic strategies have been introduced to combat COVID-19, none are fully proven or comprehensive, as several key issues and challenges remain unresolved. At present, natural products have gained significant momentum in treating metabolic disorders. Mushrooms have often proved to be the precursor of various therapeutic molecules or drug prototypes. The plentiful bioactive macromolecules in edible mushrooms, like polysaccharides, proteins, and other secondary metabolites (such as flavonoids, polyphenols, etc.), have been used to treat multiple diseases, including viral infections, by traditional healers and the medical fraternity. Some edible mushrooms with a high proportion of therapeutic molecules are known as medicinal mushrooms. In this review, an attempt has been made to highlight the exploration of bioactive molecules in mushrooms to combat the various pathophysiological complications of COVID-19. This review presents an in-depth and critical analysis of the current therapies against COVID-19 versus the potential of natural anti-infective, antiviral, anti-inflammatory, and antithrombotic products derived from a wide range of easily sourced mushrooms and their bioactive molecules.

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Background: A relevant proportion of immunocompromised patients did not reach a detectable seroconversion after a full primary vaccination cycle against SARS-CoV-2. The effect of different immunosuppressants and the potential risks for SARS-CoV-2 infection in these subjects is largely unknown. Methods: Patients from the Rivalsa prospective, observational cohort study with planned anti SARS-CoV-2 third dose mRNA vaccination between October and December 2021 were asked to participate to this follow-up study. Patients were asked about eventual confirmed positivity to SARS-CoV-2 infection within 6 months from the third dose and to undergo a blood draw to evaluate seroconversion status after the additional vaccine shot. Results: 19 out of 114 patients taking part in the survey developed a confirmed SARS-CoV-2 infection; we identified mycophenolate treatment as an independent predictor of an increased risk of infection even after the third vaccine dose (OR: 5.20, 95% CI: 1.70-20.00, p=0.0053). This result is in agreement with the in vitro evidence that MMF impairs both B and T lymphocytes driven immune responses (reduction both in memory B cells producing anti-spike antibodies and in proliferating CD4+ and CD8+ T cells). Conclusions: Immunocompromised patients need an additional vaccine administration to reach a detectable seroconversion, thus fostering a more personalized approach to their clinical management. Moreover, patients undergoing mycophenolate treatment show a specific increased infection risk, with respect to other immunosuppressants thus supporting a closer monitoring of their health status.

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PURPOSE: Low vitamin D levels were reported to negatively influence the outcome of acute COVID-19, as well as to be linked to Long-COVID. However, few studies have investigated, so far, its effects on humoral-response to anti-SARS-CoV-2 vaccination, reporting conflicting results. We aimed to evaluate the impact of baseline 25(OH)vitamin D (25(OH)D) levels on humoral-response to a two-dose cycle of Pfizer-BioNTech-vaccine up to 9-10 months after immunization. METHODS: We retrospectively included 119 consecutive healthcare-workers (median age 53 years) without a previous history of acute COVID-19 or anti-SARS-CoV-2 immunoglobulins presence immunized with two doses of Comirnaty-vaccine from January to February 2021. 25(OH)D was measured at time of first-immunization. Immune response was evaluated at: time 0 (T0), before the first-dose; T1, time of second-dose (21 days after T0); T2, T3, T4 at 1, 5 and 9 months after T1, respectively. RESULTS: Median 25(OH)D levels were 25.6 ng/mL, and vitamin D deficiency (25(OH)D <20 ng/mL) was observed in 29 subjects (24.8%). In those with vitamin D deficiency, we found a non-significant trend towards lower antibody-titers at T3, and significantly lower titers at T4 as compared to those not vitamin D-deficient, also observing a more pronounced antibody-titers negative drop from peak-T2 and T4 in those with vitamin D deficiency. A positive correlation between 25(OH)D levels and antibody-titers at T4 (p = 0.043) was found. In multiple linear-regression analysis, 25(OH)D deficiency and older-age resulted as negative independent factors associated with antibody titer at T4 (p = 0.026, p = 0.004; respectively). CONCLUSION: In our relatively young cohort presenting low prevalence of hypovitaminosis D, the long-term humoral response to anti-SARS-CoV-2 vaccination was negatively influenced by low baseline 25(OH)D. Vitamin D supplementation could be tested as a strategy to optimize the vaccination campaigns to prevent severe COVID-19.

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OBJECTIVES: Over the past 3 years, coronavirus disease 2019 with its worldwide spread has profoundly marked public health, therefore anti-COVID-19 vaccinations have been developed to prevent the dissemination of the disease. To date, 71 cases of Graves' disease (GD) after vaccination against SARS-Cov-2 were described in the adult population. Our goal is to present the first case in the paediatric population. CASE PRESENTATION: We present the first case of a 16-year-old adolescent girl who developed GD 6-7 weeks after the second dose anti-COVID-19 mRNA vaccine. Therapy with methimazole and propranolol was started, achieving normal thyroid function and negativity of thyroid autoantibodies at the time of therapy discontinuation after 8 months. CONCLUSIONS: This case shows that the development of GD after COVID-19 mRNA vaccination can occur also in the adolescent population. Nevertheless, the small number of cases of GD described so far, after many millions of vaccinations, makes it impossible to determine whether this is simple a coincidence or a cause. Further epidemiological data on the incidence of GD in the vaccination period compared to the previous period will be able to clearly define this question.

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An increasing number of breakthrough-COVID-19-vaccinated individuals are being reported across the world. Humoral immunity has a crucial role in combating infection. In this study, we aimed to assess the importance of anti-COVID-S1-IgA and anti-COVID-NP-IgA in confirmed COVID-19 after vaccination (breakthrough infection group). Blood samples were collected from the breakthrough infection group within one week of breakthrough infections (n = 34). A second sample was also collected after 4 to 8 weeks (n = 27). Blood samples of healthy individuals (n = 29) were collected 4-8 weeks after the completion of vaccination. Anti-COVID-S1-IgA and anti-COVID-NP-IgA were detected by ELISA. Statistical analysis was performed using IBM SPSS version 24. In this study, we found a higher positivity rate for anti-COVID-S1-IgA in the breakthrough infection group (70% vs. 28% in healthy individuals). Anti-COVID-NP-IgA was not found in the control group (11% in the breakthrough infection group vs. 0 in healthy individuals). In the breakthrough-infected group, the positivity rate of anti-COVID-NP-IgA decreased significantly (median titers 16.9 IU/ml decreased to 4.2 IU/ml) p = 0.001), while anti-COVID-S1-IgA increased over a period of 4-8 weeks (9.35-16.35 IU/ml). Importantly, IgA response to both COVID-19 NP and S1 antigens was not found in 13 patients at initial testing. The findings of this study show that serum IgA may have a role both in breakthrough infections and also in the prevention of severe infection. Sluggish anti-COVID-19-IgA antibody response may be responsible for the occurrence of COVID-19 infection in breakthrough infection. On the other hand, more sustained anti-COVID-19-S1-IgA over a longer period of time may have a role in preventing these patients from severe infections and hospitalization. However, a study on a larger sample size including patients with severe disease after vaccination is required to prove this hypothesis. To the best of our knowledge, this is the first study reporting the importance of serum IgA in breakthrough-infected patients from our region.

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This retrospective observational study is aimed to determine the efficacy of BNT162b2 (Pfizer-BioNTech) and CoronaVac (Sinovac) vaccines against symptomatic or severe disease in COVID-19-diagnosed patients. The secondary aim was to define the differences between vaccinated and un-vaccinated patients in terms of age, comorbidities and course of the disease, and to determine the survival rates. Of the 1463 PCR-positive patients, 55.3 % were vaccinated, and 44.7 % were unvaccinated. While 959 patients had mild-moderate symptoms, 504 patients had severe-critical symptoms and were treated in the intensive care unit. There was a statistically significant difference in the distribution of the type and doses of vaccines between the patient groups (p = 0.021). The rate of receiving 2 doses of Biontech was 18.9 % in the mild-moderate patient group but lower in the severe patient group (12.6 %). The rate of two doses of Sinovac and two doses of Biontech vaccine (four doses of vaccine) was 5 % in the mild-moderate patient group and 1.9 % in the severe patient group. The mortality rates were statistically significantly different (p < 0.001) between the patient groups: 65.3 % in the severe patient group and 1 % in the mild-moderate patient group. The multivariate model showed that the mortality risk of the unvaccinated patients was 1.5 times higher than the vaccinated ones (p = 0.042). In addition to being unvaccinated, advanced age, coronary artery disease (CAD), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), and obesity were found to be associated with higher mortality risk. Besides, the reduction in mortality rate was more evident in individuals vaccinated with at least 2 doses of the BNT162b2 (Pfizer-BioNTech) vaccine than in CoronaVac group.

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Via an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-2 spike (S) is resident in host early secretory organelles and a tiny amount is leaked out in cell surface. Only surface-exposed S can be recognized by B cell receptor (BCR) or anti-S therapeutic monoclonal antibodies (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. Now, a drug strategy to promote S host surface exposure is absent. Here, we first combined structural and biochemical analysis to characterize S COPI sorting signals. A potent S COPI sorting inhibitor was then invented, evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity (ADCC). Importantly, with the inhibitor as a probe, we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations, possibly corresponding to its ER chaperone association. Our findings not only suggest COPI is a druggable target against COVID-19, but also highlight SARS-CoV-2 evolution mechanism driven by S folding and trafficking mutations.