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1.
J Pharm Drug Res ; 3(2): 341-361, 2020.
Article in English | MEDLINE | ID: covidwho-1989782

ABSTRACT

A novel coronavirus designated as SARS-CoV-2 in February 2020 by World Health organization (WHO) was identified as main cause of SARS like pneumonia cases in Wuhan city in Hubei Province of China at the end of 2019. This been recently declared as Global Pandemic by WHO. There is a global emergency to identify potential drugs to treat the SARS-CoV-2. Currently, there is no specific treatment against the new virus. There is a urgency to identifying potential antiviral agents to combat the disease is urgently needed. An effective and quick approach is to test existing antiviral drugs against. Whole genome analysis and alignment carried out using BLASTn, SMART BLAST and WebDSV 2.0 had shown more than 238 ORF's coding for proteins mostly origin from Bat SARS coronavirus and root genomic origin from Archaea. Molecular docking results against protein targets Furin, papain like proteases, RdRp and Spike glycoprotein had shown paritaprevir, ritonavir, entecavir and chloroquine derivatives are the best drugs to inhibit multi targets of coronavirus infection including natural compounds corosolic acid, baicalin and glycyrrhizic acid with minimal inhibitory concentrations. Thus we propose use of paritaprevir, entecavir, ritonavir and chloroquine derivatives as best drug combination along with niacinamide, folic acid and zinc supplements to treat novel coronavirus infection. We also propose use of plant protease inhibitors (PI's) and Anti-IL8, IL-6, IL-2 as future drug models against coronavirus.

2.
Struct Chem ; 31(6): 2391-2412, 2020.
Article in English | MEDLINE | ID: covidwho-1906457

ABSTRACT

Presently, the SARS-CoV-2 (COVID-19) pandemic has been spreading throughout the world. Some drugs such as lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir have been recommended for COVID-19 treatment by some researchers, but these drugs were not effective enough against this virus. This study based on in silico approaches was aimed to increase the anti-COVID-19 activities of these drugs by using caulerpin and its derivatives as an adjunct drug against SARS-CoV-2 receptor proteins: the SARS-CoV-2 main protease and the SARS-CoV-2 spike protein. Caulerpin exhibited antiviral activities against chikungunya virus and herpes simplex virus type 1. Caulerpin and some of its derivatives showed inhibitory activity against Alzheimer's disease. The web server ANCHOR revealed higher protein stability for the two receptors with disordered score (< 0.6). Molecular docking analysis showed that the binding energies of most of the caulerpin derivatives were higher than all the suggested drugs for the two receptors. Also, we deduced that inserting NH2, halogen, and vinyl groups can increase the binding affinity of caulerpin toward 6VYB and 6LU7, while inserting an alkyl group decreases the binding affinity of caulerpin toward 6VYB and 6LU7. So, we can modify the inhibitory effect of caulerpin against 6VYB and 6LU7 by inserting NH2, halogen, and vinyl groups. Based on the protein disordered results, the SARS-CoV-2 main protease and SARS-CoV-2 spike protein domain are highly stable proteins, so it is quite difficult to unstabilize their integrity by using individual drugs. Also, molecular dynamics (MD) simulation indicates that binding of the combination therapy of simeprevir and the candidate studied compounds to the receptors was stable and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. So, this study suggested that caulerpin and its derivatives could be used as a combination therapy along with lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir for disrupting the stability of SARS-CoV2 receptor proteins to increase the antiviral activity of these drugs.

3.
Chem Zvesti ; 75(9): 4669-4685, 2021.
Article in English | MEDLINE | ID: covidwho-1877948

ABSTRACT

Abstract: Specific inhibition of the viral RNA-dependent RNA polymerase (RdRp) of the newly-emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising strategy for developing highly potent medicines for coronavirus disease 2019 (COVID-19). However, almost all of the reported viral RdRp inhibitors (either repurposed drugs or new antiviral agents) lack selectivity against the SARS-CoV-2 RdRp. Herein, I discovered a new favipiravir derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). Based on the significant reduction in the in vitro SARS-CoV-2 replication/copies, strong computational cyanorona-20 ligand-RdRp protein interactions, and anti-RdRp activity of the parent favipiravir drug, SARS-CoV-2 inhibition is thought to be mediated through the coronaviral-2 RdRp inhibition. This promising selective anti-COVID-19 compound is also, to the best of our knowledge, the first bioactive derivative of favipiravir, the known antiinfluenza and antiviral drug. This new nucleoside analog was designed, synthesized, characterized, computationally studied (through pharmacokinetic calculations along with computational molecular modeling and prediction), and biologically evaluated for its anti-COVID-19 activities (through a validated in vitro anti-COVID-19 assay). The results of the biological assay showed that cyanorona-20 surprisingly exhibited very significant anti-COVID-19 activity (anti-SARS-CoV-2 EC50 = 0.45 µM), and, in addition, it could be also a very promising lead compound for the design of new anti-COVID-19 agents. Cyanorona-20 is a new favipiravir derivative with promise for the treatment of SARS-CoV-2 infection. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-021-01640-9.

4.
J Ayurveda Integr Med ; 13(1): 100343, 2022.
Article in English | MEDLINE | ID: covidwho-1838942

ABSTRACT

BACKGROUND: COVID-19 is the disease caused by SARS-CoV2, it was identified in Wuhan, China, in 2019. It then extended across the globe and was termed as a pandemic in 2020. Though research work on its vaccine and drugs are carried out across the globe, it is even necessary to look over it through alternative sciences. OBJECTIVE: The objective of this study is to look over the disease through Ayurvedic perspective, analyse possible pathologies, select appropriate drugs and to study in-silico screening on these selected drugs. MATERIALS & METHODS: Available symptoms of COVID-19 were thoroughly studied and reviewed through Ayurveda classics, internet, preprints, etc. to understand the nature of the disease with the Ayurvedic perspective. The molecular Docking and Grid were generated through Pyrx Software with Autodock. The Lipinski Rule of Five data generated from Swiss ADME software and Target prediction of selected phytoconstituents were done by Swiss target prediction. RESULTS: In Ayurveda, COVID-19 can be considered as Janapadaudhwans, Va t a -Kaphaj a Sannipatik a Jwara, Aup a sargika Vyadhi, and Dhatupaka Awastha. In the molecular docking study, the binding energy and inhibition of 6 Gingesulphonic acid from Zingiber officinalis (Sunthi) is greater than hydroxychloroquine and quinine. Most of the selected phytoconstituents follow the Lipinski rule of five. Target prediction of selected phytoconstituents was done on target of SARS-CoV-2, humoral immunity, and antiviral activity. Every selected phytoconstituents works on minimum one of the targets. CONCLUSION: Thus, from the above results obtained from reviewing Ayurveda classics and after the virtual screening of selected drugs we can conclude that Nagara di Kashaya (Sunthi, Puskarmoola, Kantakari, Guduchi) may have appreciable results in combating SARS-CoV-2. Thus, Nagara di Kashayam, a classical formulation can be a trial candidate for conducting further clinical trial.

5.
J Ayurveda Integr Med ; 13(1): 100413, 2022.
Article in English | MEDLINE | ID: covidwho-1838953

ABSTRACT

BACKGROUND: Outbreak of Corona Virus Disease in late 2019 (COVID-19) has become a pandemic global Public health emergency. Since there is no approved anti-viral drug or vaccine declared for the disease and investigating existing drugs against the COVID-19. OBJECTIVE: AYUSH-64 is an Ayurvedic formulation, developed and patented by Central Council of Research in Ayurvedic Sciences, India, has been in clinical use as anti-malarial, anti-inflammatory, anti-pyretic drug for few decades. Thus, the present study was undertaken to evaluate AYUSH-64 compounds available in this drug against Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) Main Protease (Mpro; PDB ID: 6LU7) via in silico techniques. MATERIALS AND METHODS: Different molecular docking software's of Discovery studio and Auto Dock Vina were used for drugs from selected AYUSH-64 compounds against SARS-CoV-2. We also conducted 100 ns period of molecular dynamics simulations with Desmond and further MM/GBSA for the best complex of AYUSH-64 with Mpro of SARS-CoV-2. RESULTS: Among 36 compounds of four ingredients of AYUSH-64 screened, 35 observed to exhibits good binding energies than the published positive co-crystal compound of N3 pepetide. The best affinity and interactions of Akuammicine N-Oxide (from Alstonia scholaris) towards the Mpro with binding energy (AutoDock Vina) of -8.4 kcal/mol and Discovery studio of Libdock score of 147.92 kcal/mol. Further, molecular dynamics simulations with MM-GBSA were also performed for Mpro- Akuammicine N-Oxide docked complex to identify the stability, specific interaction between the enzyme and the ligand. Akuammicine N-Oxide is strongly formed h-bonds with crucial Mpro residues, Cys145, and His164. CONCLUSION: The results provide lead that, the presence of Mpro- Akuammicine N-Oxide with highest Mpro binding energy along with other 34 chemical compounds having similar activity as part of AYUSH-64 make it a suitable candidate for repurposing to management of COVID-19 by further validating through experimental, clinical studies.

6.
PLoS One ; 16(4): e0250319, 2021.
Article in English | MEDLINE | ID: covidwho-1833525

ABSTRACT

Projections of the stage of the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic and local, regional and national public health policies to limit coronavirus spread as well as "reopen" cities and states, are best informed by serum neutralizing antibody titers measured by reproducible, high throughput, and statically credible antibody (Ab) assays. To date, a myriad of Ab tests, both available and FDA authorized for emergency, has led to confusion rather than insight per se. The present study reports the results of a rapid, point-in-time 1,000-person cohort study using serial blood donors in the New York City metropolitan area (NYC) using multiple serological tests, including enzyme-linked immunosorbent assays (ELISAs) and high throughput serological assays (HTSAs). These were then tested and associated with assays for neutralizing Ab (NAb). Of the 1,000 NYC blood donor samples in late June and early July 2020, 12.1% and 10.9% were seropositive using the Ortho Total Ig and the Abbott IgG HTSA assays, respectively. These serological assays correlated with neutralization activity specific to SARS-CoV-2. The data reported herein suggest that seroconversion in this population occurred in approximately 1 in 8 blood donors from the beginning of the pandemic in NYC (considered March 1, 2020). These findings deviate with an earlier seroprevalence study in NYC showing 13.7% positivity. Collectively however, these data demonstrate that a low number of individuals have serologic evidence of infection during this "first wave" and suggest that the notion of "herd immunity" at rates of ~60% or higher are not near. Furthermore, the data presented herein show that the nature of the Ab-based immunity is not invariably associated with the development of NAb. While the blood donor population may not mimic precisely the NYC population as a whole, rapid assessment of seroprevalence in this cohort and serial reassessment could aid public health decision making.


Subject(s)
COVID-19/epidemiology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Viral/immunology , Blood Donors , COVID-19/immunology , Cohort Studies , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Immunoglobulin G/blood , Male , Middle Aged , New York City/epidemiology , SARS-CoV-2/pathogenicity , Sensitivity and Specificity , Seroconversion/physiology , Seroepidemiologic Studies , Serologic Tests/methods , Spike Glycoprotein, Coronavirus/immunology
7.
JTCVS Open ; 7: 63-71, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1740300

ABSTRACT

OBJECTIVE: The aim of this study was to model the short term and 2-year overall survival (OS) for intermediate-risk and low-risk patients with severe symptomatic aortic stenosis (AS) undergoing timely or delayed transcatheter aortic valve replacement (TAVR) during the 2019 novel coronavirus (COVID-19) pandemic. METHODS: We developed a decision analysis model to evaluate 2 treatment strategies for both low-risk and intermediate-risk patients with AS during the COVID-19 novel coronavirus pandemic. RESULTS: Prompt TAVR resulted in improved 2-year OS compared with delayed intervention for intermediate-risk patients (0.81 vs 0.67) and low-risk patients (0.95 vs 0.85), owing to the risk of death or the need for urgent/emergent TAVR in the waiting period. However, if the probability of acquiring COVID-19 novel coronavirus is >55% (intermediate-risk patients) or 47% (low-risk patients), delayed TAVR is favored over prompt intervention (0.66 vs 0.67 for intermediate risk; 0.84 vs 0.85 for low risk). CONCLUSIONS: Prompt transcatheter aortic valve replacement for both intermediate-risk and low-risk patients with symptomatic severe AS results in improved 2-year survival when local healthcare system resources are not significantly constrained by the COVID-19.

8.
J Mol Struct ; 1230: 129868, 2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1734825

ABSTRACT

In view of the recent global pandemic caused by COVID-19 intense efforts have been devoted worldwide towards the development of an effective treatment for this disease. Recently, PDE4 inhibitors have been suggested to attenuate the cytokine storm in COVID-19 especially tumour necrosis factor alpha (TNF-α). In our effort we have explored the 2-substituted pyrrolo[2,3-b]quinoxalines for this purpose because of their potential inhibitory properties of PDE-4 / TNF-α. Moreover, several of these compounds appeared to be promising in silico when assessed for their binding affinities via docking into the N-terminal RNA-binding domain (NTD) of N-protein of SARS-CoV-2. A rapid and one-pot synthesis of this class of molecules was achieved via the Cu-catalyzed coupling-cyclization-desulfinylation of 3-alkynyl-2-chloroquinoxalines with t-butyl sulfinamide as the ammonia surrogate under ultrasound irradiation. Most of these compounds showed good to significant inhibition of TNF-α in vitro establishing a SAR (Structure Activity Relationship) within the series. One compound e.g. 3i was identified as a promising hit for which the desirable ADME and acceptable toxicity profile was predicted in silico.

9.
J Virol ; 94(13)2020 06 16.
Article in English | MEDLINE | ID: covidwho-1723544

ABSTRACT

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/virology , Histocompatibility Testing/methods , Pneumonia, Viral/virology , Amino Acid Sequence , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Epitopes, T-Lymphocyte/immunology , Genetic Variation , Genotype , Haplotypes , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immunity, Innate/immunology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2 , T-Lymphocytes/immunology
10.
Chin Med J (Engl) ; 133(9): 1051-1056, 2020 May 05.
Article in English | MEDLINE | ID: covidwho-1722622

ABSTRACT

BACKGROUND: Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model. METHODS: A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively. RESULTS: The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 µmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect [EC50] of 0.98 µmol/L. The viral RNA yield in cells treated with 10 µmol/L CEP was 15,393-fold lower than in cells without CEP treatment ([6.48 ±â€Š0.02] × 10vs. 1.00 ±â€Š0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 µmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ±â€Š0.12, vs.1.00 ±â€Š0.37, t = 2.42, P < 0.05) and viral replication ([6.18 ±â€Š0.95] × 10vs. 1.00 ±â€Š0.43, t = 3.98, P < 0.05). CONCLUSIONS: Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Betacoronavirus/genetics , COVID-19 , COVID-19 Testing , Cell Line , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Drug Approval , Humans , Pandemics , Pneumonia, Viral/diagnosis , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , Viral Load
11.
J Am Soc Nephrol ; 32(9): 2147-2152, 2021 09.
Article in English | MEDLINE | ID: covidwho-1708655

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in patients with ESKD, and vaccination is hoped to prevent infection. METHODS: Between January 18 and February 24, 2021, 225 kidney transplant recipients (KTRs) and 45 patients on hemodialysis (HDPs) received two injections of mRNA BNT162b2 vaccine. The postvaccinal humoral and cellular response was explored in the first 45 KTRs and ten HDPs. RESULTS: After the second dose, eight HDPs (88.9%) and eight KTRs (17.8%) developed antispike SARS-CoV-2 antibodies (P<0.001). Median titers of antibodies in responders were 1052 AU/ml (IQR, 515-2689) in HDPs and 671 AU/ml (IQR, 172-1523) in KTRs (P=0.40). Nine HDPs (100%) and 26 KTRs (57.8%) showed a specific T cell response (P=0.06) after the second injection. In responders, median numbers of spike-reactive T cells were 305 SFCs per 106 CD3+ T cells (IQR, 95-947) in HDPs and 212 SFCs per 106 CD3+ T cells (IQR, 61-330) in KTRs (P=0.40). In KTRs, the immune response to BNT162b2 seemed influenced by the immunosuppressive regimen, particularly tacrolimus or belatacept. CONCLUSION: Immunization with BNT162b2 seems more efficient in HDPs, indicating that vaccination should be highly recommended in these patients awaiting a transplant. However, the current vaccinal strategy for KTRs may not provide effective protection against COVID-19 and will likely need to be improved.


Subject(s)
Antibodies, Viral/biosynthesis , COVID-19 Vaccines/pharmacology , COVID-19/immunology , Kidney Transplantation , Renal Dialysis , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Aged , COVID-19/complications , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , Cohort Studies , Female , Humans , Immunocompromised Host , Immunosuppressive Agents/adverse effects , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/therapy , Kidney Transplantation/adverse effects , Male , Middle Aged , Pandemics , RNA, Messenger/genetics , Retrospective Studies , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Transplant Recipients
12.
J Infect Dis ; 2021 Mar 16.
Article in English | MEDLINE | ID: covidwho-1706826

ABSTRACT

Immunoglobulin (IG) lots (N=176) released since March 2020 were tested for SARS-CoV-2 neutralizing antibodies, with first positive results for September 2020 lots, mean = 1.7 IU/ml, 46% of lots positive. From there, values steadily increased, in correlation with the cumulative COVID-19 incidence, to reach a mean of 31.2 IU/ml and 93% of lots positive by January 2021. Extrapolating the correlation, IGs could reach an anti-SARS-CoV-2 potency of ~345 IU/ml by July 2021. At that stage, prophylactic IG treatment for primary/secondary immunodeficiency could contain similar doses of anti-SARS-CoV-2 as convalescent plasma which is used for treatment of COVID-19.

13.
J Infect Dis ; 225(10): 1710-1720, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1704375

ABSTRACT

BACKGROUND: While secondary pneumococcal pneumonia occurs less commonly after coronavirus disease 2019 (COVID-19) than after other viral infections, it remains unclear whether other interactions occur between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Streptococcus pneumoniae. METHODS: We probed potential interactions between these pathogens among adults aged ≥65 years by measuring associations of COVID-19 outcomes with pneumococcal vaccination (13-valent conjugate vaccine [PCV13] and 23-valent pneumococcal polysaccharide vaccine [PPSV23]). We estimated adjusted hazard ratios (aHRs) using Cox proportional hazards models with doubly robust inverse-propensity weighting. We assessed effect modification by antibiotic exposure to further test the biologic plausibility of a causal role for pneumococci. RESULTS: Among 531 033 adults, there were 3677 COVID-19 diagnoses, leading to 1075 hospitalizations and 334 fatalities, between 1 March and 22 July 2020. Estimated aHRs for COVID-19 diagnosis, hospitalization, and mortality associated with prior PCV13 receipt were 0.65 (95% confidence interval [CI], .59-.72), 0.68 (95% CI, .57-.83), and 0.68 (95% CI, .49-.95), respectively. Prior PPSV23 receipt was not associated with protection against the 3 outcomes. COVID-19 diagnosis was not associated with prior PCV13 within 90 days following antibiotic receipt, whereas aHR estimates were 0.65 (95% CI, .50-.84) and 0.62 (95% CI, .56-.70) during the risk periods 91-365 days and >365 days, respectively, following antibiotic receipt. CONCLUSIONS: Reduced risk of COVID-19 among PCV13 recipients, transiently attenuated by antibiotic exposure, suggests that pneumococci may interact with SARS-CoV-2.


Subject(s)
COVID-19 , Pneumococcal Infections , Aged , Anti-Bacterial Agents/therapeutic use , COVID-19 Testing , Humans , Pneumococcal Infections/epidemiology , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines , Respiratory System , SARS-CoV-2 , Streptococcus pneumoniae , Vaccines, Conjugate
14.
Curr Pharmacol Rep ; 6(5): 228-240, 2020.
Article in English | MEDLINE | ID: covidwho-1682288

ABSTRACT

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for causing coronavirus disease 2019 (COVID-19), marked the third time in the twenty-first century when a new, highly pathogenic human coronavirus outbreak has led to an epidemic. The COVID-19 epidemic has emerged in late December 2019 in Wuhan city of China and spread rapidly to other parts of the world. This quick spread of SARS-CoV-2 infection to many states across the globe affecting many people has led WHO to declare it a pandemic on March 12, 2020. As of July 4, 2020, more than 523,011 people lost their lives worldwide because of this deadly SARS-CoV-2. The current situation becomes more frightening as no FDA-approved drugs or vaccines are available to treat or prevent SARS-CoV-2 infection. The current therapeutic options for COVID-19 are limited only to supportive measures and non-specific interventions. So, the need of the hour is to search for SARS-CoV-2-specific antiviral treatments and to develop vaccines for SARS-CoV-2. Also, it is equally important to maintain our immunity, and natural products and Ayurvedic medicines are indispensable in this regard. In this review, we discuss recent updates regarding various therapeutic approaches to combat COVID-19 pandemic and enlist the major pipeline drugs and traditional medicines that are under trial for COVID-19. Also, possible mechanisms involved in viral pathogenesis are discussed, which further allow us to understand various drug targets and helps in discovering novel therapeutic approaches for COVID-19. Altogether, the information provided in this review will work as an intellectual groundwork and provides an insight into the ongoing development of various therapeutic agents.

15.
Lancet ; 397(10289): 2049-2059, 2021 May 29.
Article in English | MEDLINE | ID: covidwho-1671320

ABSTRACT

BACKGROUND: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. METHODS: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. FINDINGS: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93-1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94-1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93-1·05; p=0·79). INTERPRETATION: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. FUNDING: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.


Subject(s)
COVID-19/therapy , Hospital Mortality , Length of Stay/statistics & numerical data , Aged , Aged, 80 and over , Antibodies, Viral , COVID-19/mortality , Female , Humans , Immunization, Passive/methods , Immunization, Passive/mortality , Male , Middle Aged , Pandemics , Respiration, Artificial/statistics & numerical data , SARS-CoV-2 , Treatment Outcome , United Kingdom/epidemiology
16.
Mini Rev Med Chem ; 22(2): 273-311, 2022.
Article in English | MEDLINE | ID: covidwho-1666892

ABSTRACT

Due to the high mortality rate of the 2019 coronavirus disease (COVID-19) pandemic, there is an immediate need to discover drugs that can help before a vaccine becomes available. Given that the process of producing new drugs is so long, the strategy of repurposing existing drugs is one of the promising options for the urgent treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19 disease. Although FDA has approved Remdesivir for the use in hospitalized adults and pediatric patients suffering from COVID-19, no fully effective and reliable drug has been yet identified worldwide to treat COVID-19 specifically. Thus, scientists are still trying to find antivirals specific to COVID-19. This work reviews the chemical structure, metabolic pathway, and mechanism of action of the existing drugs with potential therapeutic applications for COVID-19. Furthermore, we summarized the molecular docking stimulation of the medications related to key protein targets. These already established drugs could be further developed, and after their testing through clinical trials, they could be used as suitable therapeutic options for patients suffering from COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Metabolic Networks and Pathways/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Antiviral Agents/therapeutic use , Humans , Molecular Docking Simulation , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity
17.
Clin Infect Dis ; 74(2): 327-334, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1662105

ABSTRACT

Convalescent plasma (CP) have been used for treatment of coronavirus disease 2019 (COVID-19), but their effectiveness varies significantly. Moreover, the impact of CP treatment on the composition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 patients and antibody markers that differentiate between those who survive and those who succumb to the COVID-19 disease are not well understood. Herein, we performed longitudinal analysis of antibody profile on 115 sequential plasma samples from 16 hospitalized COVID-19 patients treated with either CP or standard of care, only half of them survived. Differential antibody kinetics was observed for antibody binding, immunoglobulin M/immunoglobulin G/immunoglobulin A (IgM/IgG/IgA) distribution, and affinity maturation in "survived" versus "fatal" COVID-19 patients. Surprisingly, CP treatment did not predict survival. Strikingly, marked decline in neutralization titers was observed in the fatal patients prior to death, and convalescent plasma treatment did not reverse this trend. Furthermore, irrespective of CP treatment, higher antibody affinity to the SARS-CoV-2 prefusion spike was associated with survival outcome. Additionally, sustained elevated IgA response was associated with fatal outcome in these COVID-19 patients. These findings propose that treatment of COVID-19 patients with convalescent plasma should be carefully targeted, and effectiveness of treatment may depend on the clinical and immunological status of COVID-19 patients, as well as the quality of the antibodies in the convalescent plasma.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive
18.
Lancet Infect Dis ; 21(10): 1383-1394, 2021 10.
Article in English | MEDLINE | ID: covidwho-1621119

ABSTRACT

BACKGROUND: Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). METHODS: We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 µg, 15 µg, or 45 µg, or one dose of sclamp vaccine at 45 µg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933. FINDINGS: Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 µg dose (geometric mean titre [GMT] 6400, 95% CI 3683-11 122), with 15 µg dose (7492, 4959-11 319), and the two 45 µg dose cohorts (8770, 5526-13 920 in the two-dose 45 µg cohort; 8793, 5570-13 881 in the single-dose 45 µg cohort); 4 weeks after the second dose (day 57) with two 5 µg doses (102 400, 64 857-161 676), with two 15 µg doses (74 725, 51 300-108 847), with two 45 µg doses (79 586, 55 430-114 268), only a single 45 µg dose (4795, 2858-8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 µg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 µg doses (GMT 228, 95% CI 146-356), two 15 µg doses (230, 170-312), and two 45 µg doses (239, 187-307). INTERPRETATION: This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. FUNDING: Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Squalene/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Australia , Female , Healthy Volunteers , Humans , Male , Pandemics/prevention & control , Polysorbates , Vaccination/adverse effects , Young Adult
19.
Eur J Neurol ; 28(10): 3230-3244, 2021 10.
Article in English | MEDLINE | ID: covidwho-1607758

ABSTRACT

BACKGROUND AND PURPOSE: An incremental number of cases of acute transverse myelitis (ATM) in individuals with ongoing or recent coronavirus disease 2019 (COVID-19) have been reported. METHODS: A systematic review was performed of cases of ATM described in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by screening both articles published and in preprint. RESULTS: Twenty cases were identified. There was a slight male predominance (60.0%) and the median age was 56 years. Neurological symptoms first manifested after a mean of 10.3 days from the first onset of classical, mostly respiratory symptoms of COVID-19. Overall, COVID-19 severity was relatively mild. Polymerase chain reaction of cerebrospinal fluid for SARS-CoV-2 was negative in all 14 cases examined. Cerebrospinal fluid findings reflected an inflammatory process in most instances (77.8%). Aquaporin-4 and myelin oligodendrocyte protein antibodies in serum (tested in 10 and nine cases, respectively) were negative. On magnetic resonance imaging, the spinal cord lesions spanned a mean of 9.8 vertebral segments, necrotic-hemorrhagic transformation was present in three cases and two individuals had additional acute motor axonal neuropathy. More than half of the patients received a second immunotherapy regimen. Over a limited follow-up period of several weeks, 90% of individuals recovered either partially or near fully. CONCLUSION: Although causality cannot readily be inferred, it is possible that cases of ATM occur para- or post-infectiously in COVID-19. All identified reports are anecdotal and case descriptions are heterogeneous. Whether the condition and the observed radiological characteristics are specific to SARS-CoV-2 infection needs to be clarified.


Subject(s)
COVID-19 , Guillain-Barre Syndrome , Myelitis, Transverse , Humans , Magnetic Resonance Imaging , Male , Middle Aged , SARS-CoV-2
20.
J Biomol Struct Dyn ; 40(1): 348-360, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1597295

ABSTRACT

The novel SARS-CoV-2 is the etiological agent causing the Coronavirus disease 2019 (COVID-19), which continues to become an inevitable pandemic outbreak. Over a short span of time, the structures of therapeutic target proteins for SARS-CoV-2 were identified based on the homology modelled structure of similar virus, SARS-CoV that transmitted rapidly in 2003. Since the outset of the disease, the research community has been looking for a potential drug lead. Out of all the known resolved structures related to SARS-CoV-2; 3-chymotrypsin (3 C) like protease (3CLpro) is considered as an attractive anti-viral drug compound on the grounds of its role in viral replication and probable non-interactive competency to bind to any viral host protein. To the best of our knowledge, till date only one compound has been identified and tested in-vitro as a potent inhibitor of 3CLpro protein, addressed as N3 (PubChem Compound CID: 6323191) and is known to bind irreversibly to 3CLpro suppressing its activity. Using computational approach, we intend to identify a probable natural fungal metabolite to interact and inhibit 3CLpro. Here after performing docking and molecular dynamics of various small molecules derived as a secondary metabolite from fungi, we propose Flaviolin as potent inhibitor of 3CLpro of novel Coronavirus SARS-CoV-2.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Fungi , Humans , Molecular Docking Simulation , Naphthoquinones , Protease Inhibitors , SARS-CoV-2
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