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2.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-329391

ABSTRACT

Background: Easily distributed oral antivirals are urgently needed to treat coronavirus disease-2019 (COVID-19), prevent progression to severe illness, and block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the results of a Phase 2a trial evaluating the safety, tolerability, and antiviral efficacy of molnupiravir in the treatment of COVID-19 ( ClinicalTrials.gov NCT04405570 ). Methods: Eligible participants included outpatients with confirmed SARS-CoV-2 infection and symptom onset within 7 days. Participants were randomized 1:1 to 200 mg molnupiravir or placebo, or 3:1 to molnupiravir (400 or 800 mg) or placebo, twice-daily for 5 days. Antiviral activity was assessed as time to undetectable levels of viral RNA by reverse transcriptase polymerase chain reaction and time to elimination of infectious virus isolation from nasopharyngeal swabs. Results: Among 202 treated participants, virus isolation was significantly lower in participants receiving 800 mg molnupiravir (1.9%) versus placebo (16.7%) at Day 3 (p = 0.02). At Day 5, virus was not isolated from any participants receiving 400 or 800 mg molnupiravir, versus 11.1% of those receiving placebo (p = 0.03). Time to viral RNA clearance was decreased and a greater proportion overall achieved clearance in participants administered 800 mg molnupiravir versus placebo (p = 0.01). Molnupiravir was generally well tolerated, with similar numbers of adverse events across all groups. Conclusions: Molnupiravir is the first oral, direct-acting antiviral shown to be highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA and has a favorable safety and tolerability profile.

3.
AIMS Biophysics ; 8(3):248-263, 2021.
Article in English | Scopus | ID: covidwho-1367953

ABSTRACT

The initial step of interaction of some pathogens with the host is driven by the interaction of glycoproteins of either side via endcaps of their glycans. These end caps consist of sialic acids or sugar molecules. Coronaviruses (CoVs), including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are found to use this route of interaction. The strength and spatial interactions on the single molecule level of sialic acids with either the spike (S) protein of SARS coronaviruses, or human angiotensin-converting enzyme 2 (ACE2) and furin are probed and compared to the binding modes of those sugar molecules which are present in glycans of glycoproteins. The protocol of using single molecules is seen as a simplified but effective mimic of the complex mode of interaction of the glycans. Averaged estimated binding energies from a docking approach result in preferential binding of the sialic acids to a specific binding site of the S protein of human coronavirus OC43 (HCoV-OC43). Furin is proposed to provide better binding sites for sialic acids than ACE2, albeit outweighed by sites for other sugar molecules. Absolute minimal estimated binding energies indicate weak binding affinities and are indifferent to the type of sugar molecules and the proteins. Neither the proposed best binding sites of the sialic acids nor those of the sugar molecules overlap with any of the cleavage sites at the S protein and the active sites of the human proteins. © 2021, AIMS Biophysics. All rights reserved.

4.
Critical Care Medicine ; 49(1):127-127, 2021.
Article in English | Web of Science | ID: covidwho-1326575
5.
Critical Care Medicine ; 49(1):84-84, 2021.
Article in English | Web of Science | ID: covidwho-1326559
6.
Aims Biophysics ; 8(2):165-181, 2021.
Article in English | Web of Science | ID: covidwho-1266794

ABSTRACT

An algorithm is applied to propose a sequence-function correlation of the transmembrane domains (TMDs) of the non-structural protein 4B (NS4B) of hepatitis C virus (HCV). The putative sequence of the TMDs is obtained using 20 available secondary structure prediction programs (SSPPs) with different lengths of the overall amino acid sequence of the protein as input. The results support the notion of four helical TMDs. Whilst the region of the first TMDs leaves room for speculation about an additional TMD, the other three TMDs are consistently predicted. Structural features and the role of each of the TMDs is proposed by applying pairwise sequence alignment using BLAST on the level (i) protein sequence alignment and consequent (ii) function-related alignment. Sequence identity with those TMDs of proteins involved in Ca-homeostasis and generation of replication vesicles, such as Nsp3 of corona viruses, murine coronavirus especially mouse hepatitis virus (MEW), middle east respiratory syndrome coronavirus (MERS), severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, are suggested. Focusing the search on those proteins in particular and their TMDs playing an active role in their mechanism of function, such as transporters, pumps, viral channel forming protein Vpu of human immunodeficiency virus type 1 (HIV-1) and mediators, suggests TMDs 2 and 4 to have functional roles in NS4B, as well as additionally TMD1 and 3 in case of vesicle formation.

7.
Topics in Antiviral Medicine ; 29(1):304-305, 2021.
Article in English | EMBASE | ID: covidwho-1250563

ABSTRACT

Background: The emergence of SARS-CoV-2 viral variants threatens current anti-viral and preventative strategies, including monoclonal antibodies and vaccines. Critically, the limited supply of vaccines and the complex logistics surrounding the delivery of infusion-based therapies herald the need for an easily produced, distributed, and specific direct-acting antiviral for COVID-19 that limits progression of illness and ideally prevents transmission. Methods: The efficacy of molnupiravir was evaluated in a double-blind, randomized, placebo-controlled, Phase 2 dose-range finding study using realtime polymerase chain reaction (RT-PCR) and virus isolation was conducted at 11 study sites in the U.S. Participants were randomized if they had signs or symptoms of COVID-19 within 7 days, and a positive SARS-CoV-2 RT-PCR within 4 days of enrollment. Initially, participants were randomized in a 1:1 ratio to receive 200 mg molnupiravir or placebo twice daily for 5 days. Subsequently, in the dose-range finding portion of the study, participants were randomized in a 3:1 ratio to receive 200, 400, or 800 mg molnupiravir or placebo twice daily for 5 days. Nasopharyngeal swabs were analyzed from 175 subjects at enrollment, Day 3, and Day 5 for SARS-CoV-2 infectivity. Samples were stored at 4°C for up to 72 hours, shipped refrigerated, aliquoted, and stored at -80°C until testing. Vero E6 cell monolayers were infected with the sample for 1 hour. Culture medium was analyzed for viral load at 2 and 5 days post-infection by RT-PCR. Results: Seventy-eight (45%) participants, median 4.62 days (min. 1.40, max. 7.54) from symptom onset, had a positive SARS-CoV-2 culture at enrollment (52 on active and 26 on placebo). The percentage of participants with a positive viral culture at enrollment who were positive on Day 3 was 20.4% on active and 28% on placebo (p = 0.56). At day 5, 24% of placebo participants were culturethe positive compared to none treated with molnupiravir (p = 0.001). Between treatment, comparisons were performed using Fisher's exact test. Conclusion: This is the first demonstration of reduced infectiousness by antiviral therapy in people with SARS-2 infection. This simple, short-course oral therapy may benefit individuals and public health and is unlikely to be impacted by spike-protein variants.

8.
Critical Care Medicine ; 49(1 SUPPL 1):127, 2021.
Article in English | EMBASE | ID: covidwho-1193966

ABSTRACT

INTRODUCTION: Severe acute respiratory failure is a common complication of COVID-19, with refractory hypoxemia being a hallmark finding in severe illness and a common cause of mortality. With limited therapeutic strategies, management centers on good supportive care. Prone positioning has been shown to improve oxygenation and survival in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) but the impact of prone positioning in COVID-19 with severe hypoxemia is unknown. This study aims to examine the response to proning as a predictor of COVID-19 related mortality. METHODS: This is a single-center, retrospective analysis of critically ill patients with COVID-19 confirmed by PCR. Patients were included if they were invasively ventilated, and if supportive care included prone positioning for management of refractory hypoxemia. Data points collected include demographics, ventilator settings, rates of mortality and progression to ECMO, ventilator-days, and time between symptom onset and intubation, hospital and ICU admission. Endpoints included response in oxygenation (PaO2:FiO2) and mortality. RESULTS: Forty-nine patients were included in the analysis. The average age was 56.9, and 61% of the patients were male. Patients had an average of 19 ventilator-days (2-52), 21 ICU-days (4-54), 26 hospital-days (8-65), an ECMO rate of 27%, and a mortality rate of 55%. Of the 22 survivors, there was an average increase in PaO2:FiO2 by 108, 93.1, and 93 for each of the first three pronations respectively. For the 27 nonsurvivors, there was an average increase in PaO2:FiO2 by 76.1, 84.3, and 50.9 for the first three pronations. The difference in improvement in PaO2:FiO2 was not statistically significant between survivors and non-survivors. There was no inflection point that could be determined that provided a high sensitivity and specificity to predict mortality or need for ECMO based on response to pronation at any of the time points. CONCLUSIONS: Proning improves PaO2:FiO2 in patients with severe hypoxemia related to COVID-19. Survivors in our study had a numerically greater response to proning, but this finding was not statistically significant. The clinical significance remains unclear. Larger studies assessing the efficacy of proning in critically ill patients with COVID-19 are needed.

9.
Critical Care Medicine ; 49(1 SUPPL 1):84, 2021.
Article in English | EMBASE | ID: covidwho-1193884

ABSTRACT

INTRODUCTION: Early commentary on SARS-CoV-2 infection proposed a mechanism of cytokine release syndrome (CRS) to explain severe acute respiratory failure associated with COVID-19. Management strategies have included targeted immunomodulation with biologic agents. The role of IL-6 and other cytokines in the pathogenesis of COVID-19 is not well defined. Evidence for use of immunomodulators has been mixed and these agents may expose patients to harm. This study aims to characterize the expression of cytokines and their association with inflammatory biomarkers and outcomes in critically ill patients with COVID-19. METHODS: This was a single-center, retrospective analysis of critically ill patients with COVID-19 confirmed by PCR. Patients were included if they had a partial or full cytokine panel drawn while admitted. Descriptive statistics were used to assess demographics, outcomes, and relationships between cytokine levels and inflammatory markers. The Mann- Whitney U Test was used to compare IL-6 levels between survivors and nonsurvivors. RESULTS: Eighty-nine patients were included with 68 full cytokine panels and 108 IL-6 levels. Patients had a mean (range) of 10 ventilator-days (0-47), 15 ICU-days (1-60), 20 hospital-days (3-69) and a mortality rate of 31%. Cytokine levels were assessed a median of 10 days from symptom onset and 1 day from ICU admission. Levels of IL-1B, IL-2, IL-4, IL-5, IL-8, IL-12, IL-13, IL-17, IFN-G, and TNF-A were undetectable in at least 80% of patients, and expression did not correlate with other inflammatory biomarkers (CRP, ferritin), severity of illness (SOFA), or outcome. IL-2R levels were numerically elevated in most patients (n=68;median 1227, range: 76-30670). IL-6 levels were mildly elevated (n=108;median: 31, range: 2-882, SD: 150), and levels were statistically significantly higher in nonsurvivors (p = 0.002). CONCLUSIONS: Assessment of cytokine levels in critically ill patients with COVID-19 does not support a hypothesis of CRS. While IL-6 levels were numerically higher in nonsurvivors, the clinical significance of this finding is unknown. The role of IL-2R in the pathogenesis of COVID-19 remains unclear. Larger studies exploring the role of inflammatory mediators in pathogenesis and targeted immunomudulators in management of COVID-19 are warranted.

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