Crafting Medical Education Differently: An Innovative Pedagogical Approach to Enhance Deep Learning in Obstetrics and Gynaecology

In this article we explore an innovative pedagogical approach initiated during the COVID-19 lockdown period to support student learning in Obstetrics and Gynaecology in the Faculty of Health Sciences at the University of Cape Town. Student isolation and the lack of exposure to clinical cases during this period brought many challenges to the teaching platform. However, the global disruption enabled an ontological opening for imaginative and creative experimentation, an aspect of teaching rarely brought into medical training. We take up the unusual work of a clinician educator and others to describe the process of developing novel video recordings for undergraduate medical students. These videos, used as pedagogical tools, enabled new ways of engaging with core curricular needs in this discipline: for the teacher, new ways of producing teaching materials, and for the students, new ways of learning medical content. The videos drew on a range of creative modes including drawing and acting, to augment student learning. As authors, we suggest that the collision of the clinical content and the performative delivery in the videos fostered deep learning and made the curricular material alive and engaging. The existence of the videos enables a sustainable blended learning approach moving forward. The uploading of the videos as Open Educational Resources onto a YouTube channel and a public website now also contribute to teaching resources extending beyond institutional boundaries. © SOTL in the South 2023.

Participatory Relationships Matter: Doctoral Students Traversing the Academy

In this article, we take our thoughts for a walk through our three different doctoral journeys and experiences with the Post Philosophies and the Doing of Inquiry Webinar Series (2020–2021). The webinars presented an example of Slow scholarship, enabling us to think deeply and differently from others and develop new ideas to take further. The online connections offered opportunities for extending learning spaces beyond traditional bounded structures. Here we explore the rich learning gained from each other's experiences of research, learning, and teaching in different higher education settings and ways in which these intersected with the webinars during the global COVID-19 pandemic. We contend that the generosity of senior academics in leadership positions who embraced global networks of communication, connected students with experts, and learned with and from their students through communal egalitarian spaces has enormous potential to support students as they traverse often demanding and challenging doctoral journeys. © The Author(s) 2022.

“There is no place like my mall”: consumer reactions to the absence of mall experiences

Purpose: How can the situation of shoppers staying at home and being unable to experience malls prepare retailers for the new marketplace? The COVID-19 lockdown provides a unique opportunity to examine the value of mall experiences to shoppers. This study aims to suggest a new mall experiences loss (MEXLOSS) model for assessing the importance of mall experiences as the foundation of any future strategy for attracting shoppers back to the mall. Design/methodology/approach: A total of 498 British shoppers completed an online survey during the May 2020 COVID-19 pandemic lockdown. Findings: When the exchanges of resources manifested in mall experiences are absent, the perceived difficulty of substituting an experience increases shoppers’ longing for the experience, which in turn increases both willingness to pay and mall loyalty but decreases well-being. Using a conceptualization of four types of mall experiences, i.e. functional, seductive, recreational and social, the functional and recreational experiences are shown to be the most valuable. Practical implications: In the new more careful service marketplace, shoppers’ preferences are increasingly oriented toward health, safety, sustainability, collaboration and digitalization. To improve their resilience and attractiveness, malls need to adjust their layout, retail mix, digitalization, activities and connectivity according to these trends and to the characteristics of each mall experience. Originality/value: To the best of the authors’ knowledge, this study is the first to place a financial value on mall experiences and to use the absence of those experiences to assess their general and relative importance. The findings challenge previous assumptions about the superiority of online shopping and the decreasing attractiveness of malls. © 2022, Emerald Publishing Limited.

From Deer-to-Deer: SARS-CoV-2 is efficiently transmitted and presents broad tissue tropism and replication sites in white-tailed deer.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) in humans, has a broad host range, and is able to infect domestic and wild animal species. Notably, white-tailed deer (WTD, Odocoileus virginianus), the most widely distributed cervid species in the Americas, were shown to be highly susceptible to SARS-CoV-2 in challenge studies and reported natural infection/exposure rates approaching 30-40% in free-ranging WTD in the U.S. Thus, understanding the infection and transmission dynamics of SARS-CoV-2 in WTD is critical to prevent future zoonotic transmission to humans, at the human-WTD interface during hunting or venison farming, and for implementation of effective disease control measures. Here, we demonstrated that following intranasal inoculation with SARS-CoV-2 B.1 lineage, WTD fawns (~8-month-old) shed infectious virus up to day 5 post-inoculation (pi), with high viral loads shed in nasal and oral secretions. This resulted in efficient deer-to-deer transmission on day 3 pi. Consistent a with lack of infectious SARS-CoV-2 shedding after day 5 pi, no transmission was observed to contact animals added on days 6 and 9 pi. We have also investigated the tropism and sites of SARS-CoV-2 replication in adult WTD (3-4 years of age). Infectious virus was detected up to day 6 pi in nasal secretions, and from various respiratory-, lymphoid-, and central nervous system tissues, indicating broad tissue tropism and multiple sites of virus replication. The study provides important insights on the infection and transmission dynamics of SARS-CoV-2 in WTD, a wild animal species that is highly susceptible to infection and with the potential to become a reservoir for the virus in the field.

From Deer-to-Deer: SARS-CoV-2 is efficiently transmitted and presents broad tissue tropism and replication sites in white-tailed deer (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 19 (COVID-19) in humans, has a broad host range, and is able to infect domestic and wild animal species. Notably, white-tailed deer (WTD, Odocoileus virginianus ) the most widely distributed cervid species in the Americas was shown to be highly susceptible to SARS-CoV-2 with reported natural infection rates approaching 40% in wild WTD populations in the U.S. Thus, understanding the infection and transmission dynamics of SARS-CoV-2 in WTD is critical to prevent future zoonotic transmission to humans and for implementation of effective disease control measures. Here, we demonstrated that following intranasal inoculation with SARS-CoV-2, deer fawns shed infectious virus up to day 5 post-inoculation (pi), with high viral loads shed in nasal and oral secretions. This resulted in efficient deer-to-deer transmission on day 3 pi. Consistent with lack of infectious SARS-CoV-2 shedding after day 5 pi, no transmission was observed to contact animals added on days 6 and 9 pi. We have also investigated the tropism and sites of SARS-CoV-2 replication in WTD. Active virus replication was observed in respiratory-, lymphoid-, and central nervous system tissues, indicating broad tissue tropism and multiple target sites of virus replication during acute infection. The study provides important insights on the infection and transmission dynamics of SARS-CoV-2 in WTD, a wild animal species that is highly susceptible to infection and with the potential to become a reservoir for the virus in the field.

Pediatric Ophthalmology Provider and Staff Attitudes and Patient Satisfaction in Telehealth Implementation During COVID-19.

Purpose:Describe a comprehensive overview of a telehealth implementation process that highlights attitudes and satisfaction scores toward telehealth from patients, providers, and staff in an academic pediatric ophthalmology practice during the early months of the coronavirus disease 2019 (COVID-19) pandemic.Methods:The electronic medical record data for telehealth and in-person visits, as well as a patient experience survey in pediatric ophthalmology were retrospectively reviewed for March 1 to July 31, 2020 and March 1 to July 31, 2019. Patient experience survey results were retrospectively reviewed. All current providers and staff were invited to participate in an anonymous and voluntary survey focused on attitudes at the time of telehealth implementation.Results:During March 1 to July 31, 2020, there was significant increase in telehealth visits (n = 1,006) compared with the same period in 2019 (n = 22). Evaluation and management (E & M) codes (n = 527) were the most commonly used billing codes, and strabismus, nystagmus, and irregular eye movement (n = 496) were the most common telehealth primary diagnoses. The telehealth attitudes survey showed more positive responses from providers than staff. The patient experience survey showed more favorable scores for telehealth visits compared with clinic visits. However, only about 50% of the respondents were satisfied with the technology in terms of ease and quality of connection during their telehealth visits.Conclusions:Telehealth was a satisfactory alternative to clinic visits in our academic pediatric ophthalmology practice during the early phase of the COVID-19 pandemic. Providers and staff had largely positive attitudes toward telehealth; however, future efforts should include strategies to increase staff buy in. Patients had high satisfaction scores with telehealth visits despite connection challenges.

Identification of Potent Small Molecule Inhibitors of SARS-CoV-2 Entry (preprint)

The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, Calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals Calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants.

Intravenous, Intratracheal, and Intranasal Inoculation of Swine with SARS-CoV-2.

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the susceptibility of animals and their potential to act as reservoirs or intermediate hosts for the virus has been of significant interest. Pigs are susceptible to multiple coronaviruses and have been used as an animal model for other human infectious diseases. Research groups have experimentally challenged swine with human SARS-CoV-2 isolates with results suggesting limited to no viral replication. For this study, a SARS-CoV-2 isolate obtained from a tiger which is identical to human SARS-CoV-2 isolates detected in New York City and contains the D614G S mutation was utilized for inoculation. Pigs were challenged via intravenous, intratracheal, or intranasal routes of inoculation (n = 4/route). No pigs developed clinical signs, but at least one pig in each group had one or more PCR positive nasal/oral swabs or rectal swabs after inoculation. All pigs in the intravenous group developed a transient neutralizing antibody titer, but only three other challenged pigs developed titers greater than 1:8. No gross or histologic changes were observed in tissue samples collected at necropsy. In addition, no PCR positive samples were positive by virus isolation. Inoculated animals were unable to transmit virus to naïve contact animals. The data from this experiment as well as from other laboratories supports that swine are not likely to play a role in the epidemiology and spread of SARS-CoV-2.

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions.

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

Experimental Inoculation of Young Calves with SARS-CoV-2.

The host range of SARS-CoV-2 and the susceptibility of animal species to the virus are topics of great interest to the international scientific community. The angiotensin I converting enzyme 2 (ACE2) protein is the major receptor for the virus, and sequence and structural analysis of the protein has been performed to determine its cross-species conservation. Based on these analyses, cattle have been implicated as a potential susceptible species to SARS-CoV-2 and have been reported to have increased ACE2 receptor distribution in the liver and kidney, and lower levels in the lungs. The goal of the current study was to determine the susceptibility of cattle to SARS-CoV-2 utilizing inoculation routes that facilitated exposure to tissues with increased ACE2 receptor distribution. For this, colostrum-deprived calves approximately 6 weeks of age were inoculated via the intratracheal or intravenous routes. Nasal and rectal swab samples, as well as blood and urine samples, were collected over the course of the study to evaluate viral shedding, viremia, and seroconversion. Pyrexia was used as the primary criteria for euthanasia and tissue samples were collected during necropsy. Importantly, SARS-CoV-2 RNA was detected in only two nasal swab samples collected on days 3 and 10 post-inoculation (pi) in two calves; one calf in the intratracheal group and the other calf in the intravenous group, respectively. Additionally, the calf in the intratracheal group that was positive on the nasal swab on day 3 pi also had a positive tracheobronchial lymph node on day 9 pi. Viral nucleic acid load on these samples, based on PCR cycle threshold values, were low and infectious virus was not recovered from the samples. These results suggest that there was no productive replication of SARS-CoV-2 in calves following intratracheal and intravenous inoculation.

Susceptibility of white-tailed deer (Odocoileus virginianus) to SARS-CoV-2.

The origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing the global coronavirus disease 19 (COVID-19) pandemic, remains a mystery. Current evidence suggests a likely spillover into humans from an animal reservoir. Understanding the host range and identifying animal species that are susceptible to SARS-CoV-2 infection may help to elucidate the origin of the virus and the mechanisms underlying cross-species transmission to humans. Here we demonstrated that white-tailed deer (Odocoileus virginianus), an animal species in which the angiotensin converting enzyme 2 (ACE2) - the SARS-CoV-2 receptor - shares a high degree of similarity to humans, are highly susceptible to infection. Intranasal inoculation of deer fawns with SARS-CoV-2 resulted in established subclinical viral infection and shedding of infectious virus in nasal secretions. Notably, infected animals transmitted the virus to non-inoculated contact deer. Viral RNA was detected in multiple tissues 21 days post-inoculation (pi). All inoculated and indirect contact animals seroconverted and developed neutralizing antibodies as early as day 7 pi. The work provides important insights into the animal host range of SARS-CoV-2 and identifies white-tailed deer as a susceptible wild animal species to the virus.IMPORTANCEGiven the presumed zoonotic origin of SARS-CoV-2, the human-animal-environment interface of COVID-19 pandemic is an area of great scientific and public- and animal-health interest. Identification of animal species that are susceptible to infection by SARS-CoV-2 may help to elucidate the potential origin of the virus, identify potential reservoirs or intermediate hosts, and define the mechanisms underlying cross-species transmission to humans. Additionally, it may also provide information and help to prevent potential reverse zoonosis that could lead to the establishment of a new wildlife hosts. Our data show that upon intranasal inoculation, white-tailed deer became subclinically infected and shed infectious SARS-CoV-2 in nasal secretions and feces. Importantly, indirect contact animals were infected and shed infectious virus, indicating efficient SARS-CoV-2 transmission from inoculated animals. These findings support the inclusion of wild cervid species in investigations conducted to assess potential reservoirs or sources of SARS-CoV-2 of infection.

Susceptibility of white-tailed deer (Odocoileus virginianus) to SARS-CoV-2 (preprint)

The origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing the global coronavirus disease 19 (COVID-19) pandemic, remains a mystery. Current evidence suggests a likely spillover into humans from an animal reservoir. Understanding the host range and identifying animal species that are susceptible to SARS-CoV-2 infection may help to elucidate the origin of the virus and the mechanisms underlying cross-species transmission to humans. Here we demonstrated that white-tailed deer (Odocoileus virginianus), an animal species in which the angiotensin converting enzyme 2 (ACE2) - the SARS-CoV-2 receptor - shares a high degree of similarity to humans, are highly susceptible to infection. Intranasal inoculation of deer fawns with SARS-CoV-2 resulted in established subclinical viral infection and shedding of infectious virus in nasal secretions. Notably, infected animals transmitted the virus to non-inoculated contact deer. Viral RNA was detected in multiple tissues 21 days post-inoculation (pi). All inoculated and indirect contact animals seroconverted and developed neutralizing antibodies as early as day 7 pi. The work provides important insights into the animal host range of SARS-CoV-2 and identifies white-tailed deer as a susceptible wild animal species to the virus. IMPORTANCEGiven the presumed zoonotic origin of SARS-CoV-2, the human-animal-environment interface of COVID-19 pandemic is an area of great scientific and public- and animal-health interest. Identification of animal species that are susceptible to infection by SARS-CoV-2 may help to elucidate the potential origin of the virus, identify potential reservoirs or intermediate hosts, and define the mechanisms underlying cross-species transmission to humans. Additionally, it may also provide information and help to prevent potential reverse zoonosis that could lead to the establishment of a new wildlife hosts. Our data show that upon intranasal inoculation, white-tailed deer became subclinically infected and shed infectious SARS-CoV-2 in nasal secretions and feces. Importantly, indirect contact animals were infected and shed infectious virus, indicating efficient SARS-CoV-2 transmission from inoculated animals. These findings support the inclusion of wild cervid species in investigations conducted to assess potential reservoirs or sources of SARS-CoV-2 of infection.

Clinical outcomes of patients with ESKD hospitalized with COVID-19

Background: Patients with end-stage kidney disease (ESKD) comprise a vulnerable population to infections. COVID-19 has been responsible for high mortality worldwide. To-date, there is limited data regarding the impact of COVID-19 in the ESKD population. We report clinical outcomes of ESKD patients with COVID-19 admitted to an academic hospital in New Orleans. Methods: We conducted an observational study in patients with ESKD and COVID-19 hospitalized at Ochsner Medical Center over a 7-week period. We compared rates of need for mechanical ventilation, shock, need for intensive care (ICU) and inhospital mortality as outcome measures between patients with and without ESKD. Results: Among 851 admissions (67% black) with COVID-19, 49 (6%) patients had diagnosis of ESKD. Patients with ESKD were mostly male [61% vs 49% in non-ESKD (n = 806), p = 0.10] with a median age of 64 (38 - 90) years. Median body mass index (BMI) were 32 vs 27 kg/m2 (p = 0.11) for those admitted to ICU vs wards, respectively. Thirteen of them (27%) vs 293 (37%) in the non-ESKD group, p=0.16) were admitted to an intensive care unit (ICU). In-hospital mortality rate for the ESKD cohort was 32% compared to 24% for non-ESKD (p = 0.21). Compared to a subset with 161 patients with acute kidney injury (AKI) with 50% mortality, the 32% mortality rate in ESKD was significantly lower (p = 0.027). Shock and/or mechanical ventilation requirement were comparable between groups [12 (24%) of those with ESKD vs 213 (26%) of non-ESKD, p = 0.65]. Median serum ferritin level was significantly more elevated in ESKD compared to non-ESKD [2125 vs 633 ng/mL, p = 0.0019). Conclusions: Clinical outcomes in individuals with ESKD with COVID19 appear to be grossly similar to that of non-ESKD population with COVID19. The similar mortality rate was seen despite higher levels of ferritin, suggesting that the interpretation of the significance of serum ferritin in ESKD has to be done with caution. Furthermore, the mortality in ESKD patients with COVID19 is lower than that observed in AKI. The observed lack of increased mortality in ESKD does not align with the outcomes of this patient population in other critical illnesses. The ability to mount and exaggerated inflammatory response in COVID19 might be somewhat restricted in ESKD.

Resource utilization and provision of in-hospital dialysis in an academic hospital in New Orleans During the COVID-19 pandemic

Background: COVID-19 has caused an ominous healthcare toll in the United States. New Orleans rated among the top affected cities. Acute kidney injury (AKI) requiring renal replacement therapy (RRT) affected 16% of COVID-19-related hospitalizations, resulting in an exponential upsurge in resource utilization related to RRT. We report our single center experience providing metrics of overall utilization and workforce expansion. Methods: We conducted a prospective collection of data of daily census of hospitalized patients with COVID-19 and AKI or ESKD for 7 weeks (3/8-4/30, 2020) quantifying usage of RRT equipment and allocation of personnel. Two independent electronic health record databases were simultaneously used to track the data. Results: Within 1 month, in-hospital COVID-19 census peaked at 377 patients, with 97 (26%) of them receiving RRT at peak day. Starting from a mean of 65 patients on RRT per day in pre-COVID-19 era, the estimated RRT growth peaked at 49%. Four out of 10 newly purchased Fresenius K2 SLED machines (FKs) were utilized by week 5 (after delivery, assembly and negative culture). Starting from an average 80% usage of baseline capacity (31 of 38 FKs), usage of 42 K2s at peak revealed 35% growth. Four new reverse osmosis devices were obtained (growth: 25 to 29, 16%) by week 5. For CVVHDF, 4 PrismaFlex machines (PFs) were rented and 10 new PrisMax were bought. Starting from an average 33% usage of baseline capacity (2 of 6 FKs), use of 6 PFs at peak meant 400% growth. Up to 30 nurses were trained virtually on RRT. Eight agency nurses and 6 perfusionists were recruited, to increase the operator number from 21 to 35 (67% growth). Five of 21 (24%) RRT nurses were out of work at peak due to COVID19+ status. One attending physician, 1 nurse practitioner and 2 subspecialty residents were added to the inpatient service, increasing the number of providers from 9 to 13 (44% growth). Conclusions: The pandemic of COVID-19 resulted in substantial increase in inhospital RRT demand and resource utilization. Our experience may provide other centers a guide to optimize preparedness in the event of facing a 'second wave' of COVID-19 in the near future. Delay in implementation has to be accounted for during strategic planning.

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to take at least 12-18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2-4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.

Oral drug repositioning candidates and synergistic remdesivir combinations for the prophylaxis and treatment of COVID-19 (preprint)

The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. A high-throughput, high-content imaging assay of human HeLa cells expressing the SARS-CoV-2 receptor ACE2 was used to screen ReFRAME, a best-in-class drug repurposing library. From nearly 12,000 compounds, we identified 66 compounds capable of selectively inhibiting SARS-CoV-2 replication in human cells. Twenty-four of these drugs show additive activity in combination with the RNA-dependent RNA polymerase inhibitor remdesivir and may afford increased in vivo efficacy. We also identified synergistic interaction of the nucleoside analog riboprine and a folate antagonist 10-deazaaminopterin with remdesivir. Overall, seven clinically approved drugs (halofantrine, amiodarone, nelfinavir, simeprevir, manidipine, ozanimod, osimertinib) and 19 compounds in other stages of development may have the potential to be repurposed as SARS-CoV-2 oral therapeutics based on their potency, pharmacokinetic and human safety profiles.

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals (preprint)

The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.