Rapamycin as a potential repurpose drug candidate for the treatment of COVID-19
Authors: Husain, Amjad; Byrareddy, Siddappa N.
The novel human coronavirus-2 (HCoV-2), called SARS-CoV-2, is the causative agent of Coronavirus Induced Disease (COVID-19) and has spread causing a global pandemic. Currently, there is no vaccine to prevent infection nor any approved drug for the treatment. The development of a new drug is time-consuming and cannot be relied on as a solution in combatting the immediate global challenge. In such a situation, the drug repurposing becomes an attractive solution to identify the potential of COVID-19 treatment by existing drugs, which are approved for other indications. Here, we review the potential use of rapamycin, an mTOR (Mammalian Target of Rapamycin) inhibitor that can be repurposed at low dosages for the treatment of COVID-19. Rapamycin inhibits protein synthesis, delays aging, reduces obesity in animal models, and inhibits activities or expression of proinflammatory cytokines such as IL-2, IL-6 and, IL-10. Overall, the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Since, rapamycin targets the host factors and not viral machinery, it represents a potent candidate for the treatment of COVID-19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA. Additionally, the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication. Therefore, by drug repurposing, low dosages of rapamycin can be tested for the potential treatment of COVID-19/SARS-CoV-2 infection.
Molecular Architecture of Early Dissemination and Massive Second Wave of the SARS-CoV-2 Virus in a Major Metropolitan Area
Authors: Long, S. Wesley; Olsen, Randall J.; Christensen, Paul A.; Bernard, David W.; Davis, James J.; Shukla, Maulik; Nguyen, Marcus; Saavedra, Matthew Ojeda; Yerramilli, Prasanti; Pruitt, Layne; Subedi, Sishir; Kuo, Hung-Che; Hendrickson, Heather; Eskandari, Ghazaleh; Nguyen, Hoang A. T.; Long, J. Hunter; Kumaraswami, Muthiah; Goike, Jule; Boutz, Daniel; Gollihar, Jimmy; McLellan, Jason S.; Chou, Chia-Wei; Javanmardi, Kamyab; Finkelstein, Ilya J.; Musser, James M.
We sequenced the genomes of 5,085 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains causing two coronavirus disease 2019 (COVID-19) disease waves in metropolitan Houston, TX, an ethnically diverse region with 7 million residents. The genomes were from viruses recovered in the earliest recognized phase of the pandemic in Houston and from viruses recovered in an ongoing massive second wave of infections. The virus was originally introduced into Houston many times independently. Virtually all strains in the second wave have a Gly614 amino acid replacement in the spike protein, a polymorphism that has been linked to increased transmission and infectivity. Patients infected with the Gly614 variant strains had significantly higher virus loads in the nasopharynx on initial diagnosis. We found little evidence of a significant relationship between virus genotype and altered virulence, stressing the linkage between disease severity, underlying medical conditions, and host genetics. Some regions of the spike protein-the primary target of global vaccine efforts-are replete with amino acid replacements, perhaps indicating the action of selection. We exploited the genomic data to generate defined single amino acid replacements in the receptor binding domain of spike protein that, importantly, produced decreased recognition by the neutralizing monoclonal antibody CR3022. Our report represents the first analysis of the molecular architecture of SARS-CoV-2 in two infection waves in a major metropolitan region. The findings will help us to understand the origin, composition, and trajectory of future infection waves and the potential effect of the host immune response and therapeutic maneuvers on SARS-CoV-2 evolution. IMPORTANCE There is concern about second and subsequent waves of COVID-19 caused by the SARS-CoV-2 coronavirus occurring in communities globally that had an initial disease wave. Metropolitan Houston, TX, with a population of 7 million, is experiencing a massive second disease wave that began in late May 2020. To understand SARS-CoV-2 molecular population genomic architecture and evolution and the relationship between virus genotypes and patient features, we sequenced the genomes of 5,085 SARS-CoV-2 strains from these two waves. Our report provides the first molecular characterization of SARS-CoV-2 strains causing two distinct COVID-19 disease waves.