Category Technology

A group from Aarhus University Hospital, Denmark, etc. has reported on efficacy of Camostat Mesilate (which is a TMPRSS2 inhibitor) for COVID-19.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060682/

Authors have investigated it through a double-blind, randomized, placebo-controlled trial. The hypothesis behind it was that TMPRSS2 inhibition would block SARS-CoV-2 replication in infected patients leading to reduced viral loads, and that this in turn would lower the risk of hyper-inflammation and prevent disease progression. However, the results from the double-blind randomized placebo-controlled trial showed that camostat mesilate treatment did not significantly improve time to clinical improvement, the risk of intubation or death, time to discontinuation of supplemental oxygen, or any other efficacy outcomes among patients hospitalized with COVID-19.

Although the dose of camostat mesilate was not optimized in this trial, but Blog Admin feels that the famous infection passway through the ACE2-TMPRSS2 initiation is not major in pulmonary epithelial cells, but there might be other infection passways through C-type lectins expressed on immune cells and phagocytosis, and so forth.

A group from Daiichi Sankyo Co., Ltd. has reported about a new chemical which is added into CHO culture media and thereby is able to improve productivity of mAbs as therapeutic drugs.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250416

Authors intended to improve productivity of mAbs with controlling those glycan modification by adding a chemical into CHO culture media.
They started screening from 23,277 chemicals, and through the following 2nd screening condition; over 120% for relative mAb concentration, 105% for relative cell-specific productivity, and 80% for viability, a few candidates were selected. From the final selectins, 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N-(2,5-dioxopyrrolidin-1-yl) benzamide (MPPB) was selected as a most suitable chemical to meet the intended requirement. MPPB concentrations of 0.32 to 0.64 mM were used, and with this addition, the productivity of mAbs increased by 1.5times.
G0F was the major N-linked glycan, and G1F was decreased from 24.5 to 14.8% under the MPPB-added condition, although others were not changed

A group from McMaster University, Canada, etc. has reported about the results of randomized clinical trial for Hydroxychloroquine, Lopinavir, Ritonavir as drugs for COVID-19.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779044

The randomized clinical trial was done in Brazil, and the sample size was as follows; A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo.
As for the virological clearance, the results were (odds ratio [OR], 0.91; 95% CI, 0.82-1.02）for hydroxychloroquine and (OR, 1.04; 95% CI, 0.94-1.16) for lopinavir-ritonavir. Neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19–associated hospitalization or other secondary clinical outcomes.

For your information,
Hydroxychloroquine：A drug used for malaria and/or rheumatoid arthritis,
Lopinavir：A drug used for HIV HAAR treatment,
Ritonavir：A drug for HIV and HCV treatment.
 

As a special case, Japanese Ministry of Health, Labor and Welfare approved “Remdesivir” as a therapeutic drug for COVID-19 in May, 2020. In Sept., 2020, Dexamathason as a corticosteroid was also approved as a therapeutic drug for COVID-19. Let me introduce a paper explaining what kinds of functional roles Dexamethason plays.

It is a paper from a group of University of Huddersfield, UK, etc.
https://link.springer.com/article/10.1007/s10753-021-01464-5

Stimulation of human PBMCs with a recombinant spike glycoprotein S1 resulted in significant release of pro-inflammatory cytokines TNFα, IL-6, IL-1β and IL-8. Pre-treatment with dexamethasone (100 nM) caused significant reduction in the release of these cytokines. SARS-CoV-2 spike glycoprotein S1 induced exaggerated inflammation in PBMCs through mechanisms involving activation of NF-κB transcription factor, p38 MAPK and the NLRP3 inflammasome, and it was found that the pre-treating PBMCs with dexamethasone inhibited NF-κB DNA binding by ～46%.

A group from University of Oxford, etc. has reported the effects of P.1 variant to therapeutic antibodies and SARS-CoV-2 vaccines.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008340/

P.1 contains the following mutations:
L18F, T20N, P26S, D138Y, and R190S in the NTD;
K417T, E484K, and N501Y in the RBD;
D614G and H655Y at the C terminus of S1;
and T1027I and V1176F in S2

Neutralization of both Lilly antibodies (LY-CoV16 and LY-CoV555) was severely impacted. There was also escape from neutralization of P.1 by Regeneron antibody (REGN10933) and a modest reduction in neutralization of P.1 by AstraZeneca antibody (AZD8895), while AstraZeneca antibodies (AZD1061 and AZD 7442) showed equal neutralization of all SARS-CoV-2 variants. The three Adagio antibodies (ADG10, ADG20, and ADG30) neutralized all variants, with all reaching a plateau at 100% neutralization; interestingly, ADG30 showed a slight increase of neutralization of P.1.

Geometric mean neutralization titers against P.1 were reduced 2.6-fold (p < 0.0001) relative to the Victoria virus for the Pfizer-BioNTech vaccine serum and 2.9-fold (p < 0.0001) for the Oxford-AstraZeneca vaccine. 

A group from Fudan University, etc. has shown that Gallocatechin gallate (GCG), a polyphenol from green tea, inhibits SARS-CoV-2 replication efficiently.
https://www.nature.com/articles/s41467-021-22297-8

SARS-CoV-2 N protein is a structural protein binding to RNA, and form a shell embracing SARS-CoV-2 RNA. This is a typical example of so called Liquid-Liquid Phase Separation (LLPS) which is a mechanism in organizing macromolecules such as proteins and RNAs into membrane-less oil droplet like organelles.
Authors has shown that GCG could could inhibit N protein LLPS in the context of SARS-CoV-2 infection effectively. Since, the amino acid sequence shares ～90% homology among corona viruses, targeting N protein by GCG could be a novel drug candidate not only for SARS-CoV-2 but also for new coronaviruses in the future.

A group from University of Colorado Denver Anschutz Medical Campus has reported that IL-1R7 antibody would be effective in COVID-19 to suppress cytokine storms.
https://www.jbc.org/article/S0021-9258(21)00416-6/fulltext

Excessive inflammation observed in macrophage activation syndrome (MAS) results in severe diseases with high mortality. The cytokine storms observed in COVID-19 patients would be a typical example similar to MAS.
Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms

IL-18 binds its specific receptor IL-1 Receptor 5 (IL-1R5, also known as IL-18 Receptor alpha chain), leading to the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7, also known as IL-18 Receptor beta chain).

Authors found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, IL-18-stimulated IFNγ production, and IL-6 production in human cell lines.

A group from Juntendo University Faculty of Medicine has reported seroprevalence of IgG and IgM antibodies in COVID-19 patients, although the cohort size was small including only 34 patients.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023454/

Using a chemiluminescent microparticle immunoassay (CMIA)-based SARS-CoV-2 IgG test (cat. # 06R90, Abbott),
Severe/Critical cases：within a week after symptom onset＝40％、1～2 weeks＝88%、after two weeks＝100％,
Mild/Moderate cases：within a week after symptom onset＝0％、1～2 weeks＝38%、after two weeks＝100％.

Using an IC IgG antibody assay using the Anti-SARS-CoV-2 Rapid Test (cat. # RTA0203, AutoBio),
Severe/Critical cases：within a week after symptom onset＝60%、1～2 weeks＝63%、after two weeks＝100%,
Mild/Moderate cases：within a week after symptom onset＝17%、1～2 weeks＝63%、after two weeks＝100%.

In this study, IgG titers remained at significantly elevated levels for 2 months, regardless of disease severity. These results indicate that IgG serologic tests could be used as a complementary test to PCR to diagnose COVID-19 from 14 days after symptom onset. However, since this cohort is so small without including asymptomatic individuals, a larger scale cohort is needed to conclude final answer.
     

A group from University of Southampton, etc. has compared site-specific glycosylation of SARS-CoV-2 spike proteins (all recombinants) among five laboratories.
The cells used for Sproten expression were as follows.
HEK293： Amsterdam, Harvard,
HEK293F： Southampton/Texas,
HEK293T： Oxford,
CHO： Swiss,
It is celarly shown that site-specific glycosylation changes considerablly with reflecting differences in cells and culture conditions.
Fundamentally speaking, it is a mixture of oligo mannose and complex type N-glycans.

Blog admin is interested in how much these differences cause difference in the infectivity, how glycosylation changes with SARS-CoV-2 mutations, and how much the glycosylation changes due to mutations affect the infectivity.
https://www.biorxiv.org/content/10.1101/2021.03.08.433764v1.full

A group from German Primate Center, Göttingen, etc. has reported on the effectiveness of major monoclonal antibodies for COVID-19 (Casirivimab, Bamlanivimab, Imdevimab）against SARS-CoV-2 variants, that of a cocktail monoclonal antibody (REGN-COV2: consisting of Casirivimab and Imdevimab), and also that of Pfizer BNT162b2 vaccine against those variants.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980144/

A cocktail monoclonal antibody (REGN-COV2）efficiently inhibited infection mediated by the S proteins of all variants (B.1.1.7, B.1.351, P.1). However, infection mediated by the S proteins of the B.1.351 and P.1 variant was completely resistant to REGN10989 and Bamlanivimab.

On the other hand, the Pfizer BNT162b2 vaccine is based on an mRNA that encodes for the SARS-CoV-2 S protein and is said to be highly protective against COVID-19. All sera from 15 donors immunized twice with BNT162b2 efficiently inhibited entry driven by the WT S protein and inhibition of entry driven by the S protein of the B.1.1.7 variant was only slightly reduced. However, 12 out of 15 sera showed a markedly reduced inhibition of entry driven by the S proteins of the B.1.351 and P.1 variants