scholarly journals Discovery of highly potent pancoronavirus fusion inhibitors that also effectively inhibit COVID-19 variants from the UK and South Africa

2021 ◽  
Author(s):  
Francesca Curreli ◽  
Shahad Ahmed ◽  
Sofia M. B. Victor ◽  
Aleksandra Drelich ◽  
Siva S. Panda ◽  
...  
Keyword(s):  
South Africa ◽  
Benzoic Acid ◽  
Spike Protein ◽  
Fusion Inhibitors ◽  
Resident Time ◽  
Orally Bioavailable ◽  
The Uk ◽  
Lead Inhibitors ◽  
Further Development

We report the discovery of a series of benzoic acid-based inhibitors that show highly potent pancoronavirus activity. Some compounds also show complete inhibition of CPE (IC100) at 1.25 μM against an authentic SARS-CoV-2 (US_WA-1/2020). Furthermore, the most active inhibitors also potently inhibited variants initially identified in the UK and South Africa. We confirmed that one of the potent inhibitors binds to the prefusion spike protein trimer of SARS-CoV-2 by SPR. Besides, we showed that they inhibit virus-mediated cell-cell fusion. The ADME data show druglike characteristics, and in vivo PK in rats demonstrated excellent half-life (t½) of 11.3 h, mean resident time (MRT) of 14.2 h, and orally bioavailable. Despite the presence of ene-rhodamine moiety, we conclusively demonstrated that these inhibitors target the viral spike protein and are not promiscuous or colloidal aggregators. We expect the lead inhibitors to pave the way for further development to preclinical and clinical candidates.

scholarly journals Discovery of Highly Potent Fusion Inhibitors with Potential Pan-Coronavirus Activity That Effectively Inhibit Major COVID-19 Variants of Concern (VOCs) in Pseudovirus-Based Assays

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 69
Author(s):  
Francesca Curreli ◽  
Shahad Ahmed ◽  
Sofia M. B. Victor ◽  
Aleksandra Drelich ◽  
Siva S. Panda ◽  
...  
Keyword(s):  
Small Molecules ◽  
South African ◽  
Inhibitory Concentration ◽  
Cytopathic Effects ◽  
Fusion Inhibitors ◽  
Resident Time ◽  
The Uk ◽  
Lead Inhibitors ◽  
Further Development

We report the discovery of several highly potent small molecules with low-nM potency against severe acute respiratory syndrome coronavirus (SARS-CoV; lowest half-maximal inhibitory concentration (IC50: 13 nM), SARS-CoV-2 (IC50: 23 nM), and Middle East respiratory syndrome coronavirus (MERS-CoV; IC50: 76 nM) in pseudovirus-based assays with excellent selectivity index (SI) values (>5000), demonstrating potential pan-coronavirus inhibitory activities. Some compounds showed 100% inhibition against the cytopathic effects (CPE; IC100) of an authentic SARS-CoV-2 (US_WA-1/2020) variant at 1.25 µM. The most active inhibitors also potently inhibited variants of concern (VOCs), including the UK (B.1.1.7) and South African (B.1.351) variants and the Delta variant (B.1.617.2) originally identified in India in pseudovirus-based assay. Surface plasmon resonance (SPR) analysis with one potent inhibitor confirmed that it binds to the prefusion SARS-CoV-2 spike protein trimer. These small-molecule inhibitors prevented virus-mediated cell–cell fusion. The absorption, distribution, metabolism, and excretion (ADME) data for one of the most active inhibitors, NBCoV1, demonstrated drug-like properties. An in vivo pharmacokinetics (PK) study of NBCoV1 in rats demonstrated an excellent half-life (t1/2) of 11.3 h, a mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect these lead inhibitors to facilitate the further development of preclinical and clinical candidates.

scholarly journals Cornering an Ever-Evolving Coronavirus: TATX-03, a fully human synergistic multi-antibody cocktail targeting the SARS-CoV-2 Spike Protein with in vivo efficacy

2021 ◽  
Author(s):  
Ilse Roodink ◽  
Maartje van Erp ◽  
Andra Li ◽  
Sheila Potter ◽  
Sander Martinus Johannes van Duijnhoven ◽  
...  
Keyword(s):  
Therapeutic Strategies ◽  
Spike Protein ◽  
Health Crisis ◽  
In Vivo Efficacy ◽  
The Individual ◽  
Further Development ◽  
Therapeutic Administration ◽  
Antibody Cocktail

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an ongoing global human health crisis and will likely become endemic, requiring novel sustainable therapeutic strategies. We report on the discovery of a fully human multi-antibody cocktail (TATX-03) targeting diversified non-overlapping epitopes on the SARS-CoV-2 spike protein that suppressed replication-competent viral titers to undetectable levels in the lungs of SARS-CoV-2 challenged hamsters upon both prophylactic and therapeutic administration. While monotherapy with two of the individual cocktail components also showed clear in vivo protection, neither recapitulated the efficacy of TATX-03. This synergistic effect was further supported by examining in vivo efficacy of these individual antibodies and corresponding combination therapy at a lower dose. Furthermore, in vitro screenings using VSV-particles pseudo-typed with spike proteins representing the SARS-CoV-2 variants of concern Alpha, Beta, and Delta showed that TATX-03 maintained its neutralization potency. These results merit further development of TATX-03 as a potential therapy for SARS-CoV-2 infection with resistance to mutagenic escape.

scholarly journals Protein-based RBD-C-tag COVID-19 Vaccination Candidate Elicits Protection Activity against SARS-COV-2 Variant Infection

2021 ◽  
Author(s):  
Jaganathan Subramani ◽  
Namir Shaabani ◽  
Dhwani Shetty ◽  
Haiwa Wu ◽  
Sunkuk Kwon ◽  
...  
Keyword(s):  
South Africa ◽  
T Cells ◽  
Aluminum Phosphate ◽  
Spike Protein ◽  
Igg Antibodies ◽  
Th1 Polarization ◽  
Protection Activity ◽  
Virus Strains

ABSTRACTThe identification of a vaccination candidate against COVID-19 providing protecting activity against emerging SARS-COV-2 variants remains challenging. Here, we report protection activity against a spectrum of SARS-COV-2 and variants by immunization with protein-based recombinant RBD-C-tag administered with aluminum-phosphate adjuvant intramuscularly. Immunization of C57BL/6 mice with RBD-C-tag resulted in the in vivo production of IgG antibodies recognizing the immune-critical spike protein of the SARS-COV-2 virus as well as the SARS-COV-2 variants alpha (“United Kingdom”), beta (“South Africa”), gamma (“Brazil/Japan”), and delta (“India”) as well as wt-spike protein. RBD-C-tag immunization led to a desired Th1 polarization of CD4 T cells producing IFNγ. Importantly, RBD-C-tag immunization educated IgG production delivers antibodies that exert neutralizing activity against the highly transmissible SARS-COV-2 virus strains “Washington”, “South Africa” (beta), and “India” (delta) as determined by conservative infection protection experiments in vitro. Hence, the protein-based recombinant RBD-C-tag is considered a promising vaccination candidate against COVID-19 and a broad range of emerging SARS-COV-2 virus variants.

scholarly journals Effects of common mutations in the SARS-CoV-2 Spike RBD domain and its ligand the human ACE2 receptor on binding affinity and kinetics

2021 ◽  
Author(s):  
Michael I Barton ◽  
Stuart MacGowan ◽  
Mikhail A Kutuzov ◽  
Omer Dushek ◽  
Geoffrey J Barton ◽  
...  
Keyword(s):  
South Africa ◽  
Cell Surface ◽  
Immune Escape ◽  
Surface Protein ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Cell Surface Protein ◽  
Kinetics Analysis ◽  
Protein Receptor ◽  
The Uk

The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD domain are present in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the more transmissible B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD domain that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K and S477N) and two common ACE2 mutations (S19P and K26R) on the RBD/ACE2 interaction. We analysed the effects of individual RBD mutations, and combinations found in new SARS-CoV-2 variants first identified in the UK (B.1.1.7), South Africa (B.1.351) and Brazil (P1). Most of these mutations increased the affinity of the RBD/ACE2 interaction. The exceptions were mutations K417N/T, which decreased the affinity. Taken together with other studies, our results suggest that the N501Y and S477N mutations primarily enhance transmission, the K417N/T mutations facilitate immune escape, and the E484K mutation facilitates both transmission and immune escape.

International Listening Post report summary: the world at the dawn of 2019

2019 ◽  
Vol 19 (1) ◽  
pp. 121-124
Author(s):  
Sandy Henderson ◽  
Ulrike Beland ◽  
Dimitrios Vonofakos
Keyword(s):  
South Africa ◽  
Faroe Islands ◽  
The South ◽  
The World ◽  
The Uk

On or around 9 January 2019, twenty-two Listening Posts were conducted in nineteen countries: Canada, Chile, Denmark, Faroe Islands, Finland, Germany (Frankfurt and Berlin), Hungary, India, Ireland, Israel, Italy (two in Milan and one in the South), Peru, Serbia, South Africa, Spain, Sweden, Taiwan, Turkey, and the UK. This report synthesises the reports of those Listening Posts and organises the data yielded by them into common themes and patterns.

Good Governance

2019 ◽  
Author(s):  
Henk Addink
Keyword(s):  
South Africa ◽  
Rule Of Law ◽  
Good Governance ◽  
National Level ◽  
Administrative Law ◽  
Modern State ◽  
The Rule Of Law ◽  
The Third ◽  
Legal Perspective ◽  
Further Development

The pivotal aim of this book is to explain the creation, development, and impact of good governance from a conceptual, principal perspective and in the context of national administrative law. Three lines of reasoning have been worked out: developing the concept of good governance; specification of this concept by developing principles of good governance; and implementation of these principles of good governance on the national level. In this phase of further development of good governance, it is important to have a clear concept of good governance, presented in this book as the third cornerstone of a modern state, alongside the concepts of the rule of law and democracy. That is a rather new national administrative law perspective which is influenced by regional and international legal developments; thus, we can speak about good governance as a multilevel concept. But the question is: how is this concept of good governance further developed? Six principles of good governance (which in a narrower sense also qualify as principles of good administration) have been further specified in a systematic way, from a legal perspective. These are the principles of properness, transparency, participation, effectiveness, accountability, and human rights. Furthermore, the link has been made with integrity standards. The important developments of each of these principles are described on the national level in Europe, but also in countries outside Europe (such as Australia, Canada, and South Africa). This book gives a systematic comparison of the implementation of the principles of good governance between countries.

scholarly journals Drivers of Broad-Spectrum Antibiotic Overuse across Diverse Hospital Contexts—A Qualitative Study of Prescribers in the UK, Sri Lanka and South Africa

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 94
Author(s):  
Carolyn Tarrant ◽  
Andrew M. Colman ◽  
David R. Jenkins ◽  
Edmund Chattoe-Brown ◽  
Nelun Perera ◽  
...  
Keyword(s):  
South Africa ◽  
Sri Lanka ◽  
Antimicrobial Stewardship ◽  
Broad Spectrum ◽  
Low Income ◽  
System Level ◽  
Comparative Approach ◽  
Structured Interviews ◽  
Public And Private ◽  
The Uk

Antimicrobial stewardship programs focus on reducing overuse of broad-spectrum antibiotics (BSAs), primarily through interventions to change prescribing behavior. This study aims to identify multi-level influences on BSA overuse across diverse high and low income, and public and private, healthcare contexts. Semi-structured interviews were conducted with 46 prescribers from hospitals in the UK, Sri Lanka, and South Africa, including public and private providers. Interviews explored decision making about prescribing BSAs, drivers of the use of BSAs, and benefits of BSAs to various stakeholders, and were analyzed using a constant comparative approach. Analysis identified drivers of BSA overuse at the individual, social and structural levels. Structural drivers of overuse varied significantly across contexts and included: system-level factors generating tensions with stewardship goals; limited material resources within hospitals; and patient poverty, lack of infrastructure and resources in local communities. Antimicrobial stewardship needs to encompass efforts to reduce the reliance on BSAs as a solution to context-specific structural conditions.

scholarly journals Immunization with RBD-P2 and N protects against SARS-CoV-2 in nonhuman primates

2021 ◽  
Vol 7 (22) ◽  
pp. eabg7156
Author(s):  
So-Hee Hong ◽  
Hanseul Oh ◽  
Yong Wook Park ◽  
Hye Won Kwak ◽  
Eun Young Oh ◽  
...  
Keyword(s):  
Nucleocapsid Protein ◽  
Nonhuman Primates ◽  
Vaccine Candidate ◽  
Statistical Significance ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Vaccine Candidates ◽  
Cell Responses ◽  
Antibody Levels ◽  
Further Development

Since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), various vaccines are being developed, with most vaccine candidates focusing on the viral spike protein. Here, we developed a previously unknown subunit vaccine comprising the receptor binding domain (RBD) of the spike protein fused with the tetanus toxoid epitope P2 (RBD-P2) and tested its efficacy in rodents and nonhuman primates (NHPs). We also investigated whether the SARS-CoV-2 nucleocapsid protein (N) could increase vaccine efficacy. Immunization with N and RBD-P2 (RBDP2/N) + alum increased T cell responses in mice and neutralizing antibody levels in rats compared with those obtained using RBD-P2 + alum. Furthermore, in NHPs, RBD-P2/N + alum induced slightly faster SARS-CoV-2 clearance than that induced by RBD-P2 + alum, albeit without statistical significance. Our study supports further development of RBD-P2 as a vaccine candidate against SARS-CoV-2. Also, it provides insights regarding the use of N in protein-based vaccines against SARS-CoV-2.

scholarly journals Shape-shifting and pushing against the odds: staff perceptions of the experiences of first generation students in South Africa and the UK

2021 ◽  
Author(s):  
Rachel Forsyth ◽  
Claire Hamshire ◽  
Danny Fontaine-Rainen ◽  
Leza Soldaat
Keyword(s):  
Higher Education ◽  
South Africa ◽  
First Generation ◽  
Teaching Practice ◽  
First Generation Students ◽  
Staff Perceptions ◽  
Staff Members ◽  
Diversity And Inclusion ◽  
University Life ◽  
The Uk

AbstractThe principles of diversity and inclusion are valued across the higher education sector, but the ways in which these principles are translated into pedagogic practice are not always evident. Students who are first in their family to attend university continue to report barriers to full participation in university life. They are more likely to leave their studies early, and to achieve lower grades in their final qualifications, than students whose families have previous experience of higher education. The purpose of this study was to explore whether a mismatch between staff perceptions and students’ experiences might be a possible contributor to these disparities. The study explored and compared staff discourses about the experiences of first generation students at two universities, one in the United Kingdom (UK), and the other in South Africa (SA). One-to-one interviews were carried out with 40 staff members (20 at each institution) to explore their views about first generation students. The results showed that staff were well aware of challenges faced by first generation students; however, they were unsure of their roles in relation to shaping an inclusive environment, and tended not to consider how to use the assets that they believed first generation students bring with them to higher education. This paper explores these staff discourses; and considers proposals for challenging commonly-voiced assumptions about students and university life in a broader context of diversity and inclusive teaching practice.

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