Design of D-amino acids SARS-CoV-2 Main protease inhibitors using the cationic peptide from rattlesnake venom as a scaffold

The C30 Endopeptidase (3C-like protease; 3CLpro) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and is hence a promising drug target. Molecules isolated from animals, insects, plants or microorganisms can serve as a scaffold for the design of novel biopharmaceutical products. Crotamine, a small cationic peptide from the venom of the rattlesnake Crotalus durissus terrificus has been the focus of many studies since it exhibits activities such as analgesic, in vitro antibacterial and hemolytic activities. The crotamine derivative L-peptides (L-CDP) that inhibit the 3CL protease in the low {micro}M range were examined since they are susceptible to proteolytic degradation; we explored the utility of their D-enantiomers form. Comparative uptake inhibition analysis showed D-CDP as a promising prototype for a D-peptide-based drug. We also found that the D-peptides can impair SARS-CoV-2 replication in vivo, probably targeting the viral protease 3CLpro.

A combined strategy to detect plasma samples reliably with high anti-SARS-CoV-2 neutralizing antibody titers in routine laboratories

The determination of anti-SARS-CoV-2 neutralizing antibodies (NAbs) is of interest in many respects. High NAb titers, for example, are the most important criterion regarding the effectiveness of convalescent plasma therapy. However, common cell culture-based NAb assays are time-consuming and feasible only in special laboratories. Our data reveal the suitability of a novel ELISA-based surrogate virus neutralization test (sVNT) to easily measure the inhibition-capability of NAbs in the plasma of COVID-19 convalescents. We propose a combined strategy to detect plasma samples with high NAb titers ([≥] 1:160) reliably and to, simultaneously, reduce the risk of erroneously identifying low-titer specimens. For this approach, results of the sVNT assay are compared to and combined with those acquired from the Euroimmun anti-SARS-CoV-2 IgG assay. Both assays are appropriate for high-throughput screening in standard BSL-2 laboratories. Our measurements further show a long-lasting humoral immunity of at least 11 months after symptom onset.

From COVID-19 to the Common Cold: Novel Host-Targeted, Pan-Respiratory Antiviral Small Molecule Therapeutics

We present a small molecule chemotype, identified by an orthogonal drug screen, exhibiting nanomolar activity against members of all the six viral families causing most human respiratory viral disease, with a demonstrated barrier to resistance development. Antiviral activity is shown in mammalian cells, including human primary bronchial epithelial cells cultured to an air-liquid interface and infected with SARS-CoV-2. In animals, efficacy of early compounds in the lead series is shown by survival (for a coronavirus) and viral load (for a paramyxovirus). The drug target is shown to include a subset of the protein 14-3-3 within a transient host multi-protein complex containing components implicated in viral lifecycles and in innate immunity. This multi-protein complex is modified upon viral infection and largely restored by drug treatment. Our findings suggest a new clinical therapeutic strategy for early treatment upon upper respiratory viral infection to prevent progression to lower respiratory tract or systemic disease. One Sentence SummaryA host-targeted drug to treat all respiratory viruses without viral resistance development.

Sensitivity of commercial Anti-SARS-CoV-2 serological assays in a high-prevalence setting

We analysed SARS-CoV-2 specific antibody responses in 42 social and working contacts of a super-spreader from the Heinsberg area in Germany. Consistent with a high-prevalence setting 26 individuals had SARS-CoV-2 antibodies determined by in-house neutralisation testing. These results were compared with four commercial assays, suggesting limited sensitivity of the assays in such a high-prevalence setting. Although SARS-CoV-2 nucleocapsid-restricted tests showed a better sensitivity, spike-based assays had a stronger correlation with neutralisation capacity.

SARS-CoV-2 targets cortical neurons of 3D human brain organoids and shows neurodegeneration-like effects

COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Dusseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within two days of exposure. Using COVID-19 convalescent serum, we identified that SARS-CoV-2 preferably targets soma of cortical neurons but not neural stem cells, the target cell type of ZIKA virus. Imaging cortical neurons of organoids reveal that SARS-CoV-2 exposure is associated with missorted Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Surprisingly, SARS-CoV-2 co-localizes specifically with Tau phosphorylated at Threonine-231 in the soma, indicative of early neurodegeneration-like effects. Our studies, therefore, provide initial insights into the impact of SARS-CoV-2 as a neurotropic virus and emphasize that brain organoids could model CNS pathologies of COVID-19. One sentence summaryCOVID-19 modeling in human brain organoids

Changing Gender Norms and Reducing HIV and Violence Risk Among Workers and Students in China.

Global evidence demonstrates that inequitable gender norms negatively influence key health outcomes (e.g., violence, HIV/STI), and the importance of male involvement in prevention efforts. The China Family Planning Association and PATH partnered to develop and evaluate a gender-focused behavior change communication intervention for HIV and violence prevention. Eight participatory education sessions-adapted for the Chinese setting-were implemented in factories and schools. Baseline and endline surveys with participants (219 male factory workers and 496 male vocational students) were conducted. Support for (in)equitable norms was measured by the Gender Equitable Men Scale, as well as partner violence and communication. Focus groups with male and female workers/students, teachers, and factory managers were used to corroborate findings. At baseline, many workers and students supported inequitable gender norms, with workers generally being more inequitable. At endline, significant positive changes in gender-related views (e.g., reduction from 42% to 18% of workers agreeing that "a woman should tolerate violence in order to keep her family together") and behaviors (e.g., reduction from 15% to 7% of students reporting partner violence over the past 3 months) were reported. Results suggest that a relatively low intensity intervention can influence important gender norms and related behaviors.

Factors influencing the acquisition and correct and consistent use of the top-lit updraft cookstove in Uganda.

This study looked at the effects of select behavior change interventions on the purchase and the correct and consistent use of a locally fabricated top-lit updraft (TLUD) stove in Uganda. Behavior change interventions included training of community sales agents and village health team volunteers on household air pollution and correct use, referral of interested community members to sales agents, community cooking demonstrations, information flyers, and direct sales of TLUDs and processed wood. Qualitative and quantitative research methods shaped interventions and were used to understand attitudes and practices related to TLUD stove acquisition and use. Results showed that TLUDs were appreciated because they use wood efficiently, cook quickly, reduce smoke, and produce charcoal. However, the substantial purchase price barrier, combined with the cost of processed wood, effectively eliminated the cost savings from its significant fuel efficiency. This made it difficult for the TLUD to be a meaningful part of most households' cooking practices.