Basic Science Drug Design

The FDA-approved gold drug auranofin inhibits novel coronavirus (SARSCOV-2) replication and attenuates inflammation in human cells

 

This study reports that the FDA-approved drug, auranofin, inhibits SARS-COV-2 replication in human cells at low micro molar concentration. Treatment of cells with auranofin resulted in a 95% reduction in the viral RNA at 48 hours after infection. 

 

Rothan, H. A., Stone, S., Natekar, J., Kumari, P., Arora, K., & Kumar, M. (2020). The FDA-approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells. Virology.

Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease

Successful discovery of new chemical entities for treatment of SARS-CoV-2 will hugely depend on proper understanding of the structure, interactions and dynamics of validated targets and the unexplored potential of their binding sites to bind new chemotypes. Computational methods have become indispensable for infectious disease drug discovery in last few decades not only to understand the drug-target interactions and delineate the structure activity relationship of small

druglike molecules, but also for screening huge chemical libraries providing a fast and less expensive alternative to the traditional high throughput screening. Among a plethora of computational drug design strategies, fragment based de novo design of molecule has gained immense popularity. As starting points, they provide profound opportunity for subsequent optimization leading to chemical entities with improved pharmacokinetic properties compared to molecules obtained as hits from high throughput screenings.

Chinmayee Choudhury (2020) Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease, Journal of Biomolecular Structure and Dynamics,

DOI:  10.1080/07391102.2020.1771424

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

Drug repurposing, representing an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV–host interactome and drug targets in the human protein–protein interaction network. Using

network proximity analyses of drug targets and HCoV–host interactions in the human interactome, this study prioritizes 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. 

Zhou, Y., Hou, Y., Shen, J., Huang, Y., Martin, W., & Cheng, F. (2020). Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell discovery, 6(1), 1-18.

Basic Science Vaccine

DNA vaccine protection against SARS-CoV-2 in rhesus macaques

This study came out of Beth Israel Deaconess, with a larger cohort of 35 rhesus macaques. The authors tested 6 different DNA constructs for S protein domains in parallel, and there is an interesting difference in upper respiratory versus lower respiratory protection between constructs. The DNA vaccines induced a Th1-type rather than Th2-mediated response. No nucleic acid vaccines have been FDA approved to date, and while nucleic acid vaccines provide good design flexibility, they rely on a target with relatively low mutation rates. Also of note, the pseudovirus challenges generally provoked a stronger humoral response than live virus.

Yu, J., Tostanoski, L. H., Peter, L., Mercado, N. B., McMahan, K., Mahrokhian, S. H., ... & Martinez, D. R. (2020). DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science.

Translational Science

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

This study describes the results of an open-label, non randomized phase 1 trial dose escalation trial of a SARS-CoV-2 vaccine candidate. Specifically the SARS-CoV-2 spike protein was engineered to be expressed by a type-5 adenoviral vector, and a single low, medium, or high dose of viral particles was given to healthy subjects. 108 patients were enrolled on study, and followed over a course of 28 days following vaccination; treatment groups were similar in gender and age distribution. In summary, this vaccine candidate is demonstrated to be mostly safe, and is effective. A follow-up phase 2 study is underway.

Zhu, Feng-Cai, et al. "Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial." The Lancet (2020).

Development of an inactivated vaccine candidate for SARS-CoV-2

In this study the authors developed an inavtivated SARS-CoV-2 vaccine candidate and demonstrated the agent to confer immunity to the virus in murine and NHP models (quantification of antibody response). Further evaluation was done in the context of a NHP model of COVID 19 that mimics human pathophysiology, wherin animals were challenged with SARS-CoV-2 ad 22 days following vaccination, and both high and low doses of vaccine candidate were able to reduce viral load as compared to placebo and sham treated animals.

Gao, Q., Bao, L., Mao, H., et al. (2020). Development of an inactivated vaccine candidate for SARS-CoV-2. Science.

Public Health

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Hydroxychloroquine or chloroquine with azithromycin, in addition to being ineffective at treating SARS-CoV-2 infections, actually might cause more harm and death. 

Mehra, Mandeep R., et al. "Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis." The Lancet (2020).