Carrimycin for COVID-19

Abstract The -1 programmed ribosomal frameshifting (-1 PRF) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for keeping the balance between pp1a and pp1ab polyproteins. To date, the host factors influencing this process remain poorly understood. Using RNA pull-down assays combined with mass spectrometry screening, we discovered five host proteins interacting with -1 PRF RNA, including Stem Loop Binding Protein (SLBP). Our findings revealed that SLBP overexpression enhanced frameshifting and promoted viral replication. Moreover, the interaction between SLBP and -1 PRF RNA was predicted using the PrismNet deep learning tool, which calculated a high binding probability of 0.922. Using Electrophoretic Mobility Shift Assays (EMSAs) and RNA pull down assays, our findings demonstrated SLBP’s direct binding to the SARS-CoV-2 genome, with preferential affinity for the stem loop 3 region of the -1 PRF RNA. Using smFISH assays, we further confirmed their physical colocalization. The role of SLBP in promoting frameshifting was verified using an in vitro translation system. Further investigation showed that SLBP deletions reshaped the host factor pattern around -1 PRF RNA, diminishing interactions with FUBP3 and RPS3A while enhancing RPL10A binding. Together, our findings identify SLBP as a host protein that promotes SARS-CoV-2 frameshifting, highlighting its potential as a druggable target for COVID-19.

AbstractThe outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies and economies. Until now, effective therapeutics against COVID-19 are in high demand. Along with our improved understanding of the structure, function, and pathogenic process of SARS-CoV-2, many small molecules with potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition of viral proteins such as RdRp and Mpro, interference of host enzymes including ACE2 and proteases, and blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, and NLRP3 pathways, are regarded feasible in drug development. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy. Several small molecules representative by remdesivir and paxlovid have been proved or authorized emergency use in many countries. And many candidates have entered clinical-trial stage. Nevertheless, due to the epidemiological features and variability issues of SARS-CoV-2, it is necessary to continue exploring novel strategies against COVID-19. This review discusses the current findings in the development of small molecules for COVID-19 treatment. Moreover, their detailed mechanism of action, chemical structures, and preclinical and clinical efficacies are discussed.

According to the World Health Organization (WHO), in the second half of 2022, there are about 606 million confirmed cases of COVID-19 and almost 6,500,000 deaths around the world. A pandemic was declared by the WHO in March 2020 when the new coronavirus spread around the world. The short time between the first cases in Wuhan and the declaration of a pandemic initiated the search for ways to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to attempt to cure the disease COVID-19. More than ever, research groups are developing vaccines, drugs, and immunobiological compounds, and they are even trying to repurpose drugs in an increasing number of clinical trials. There are great expectations regarding the vaccine’s effectiveness for the prevention of COVID-19. However, producing sufficient doses of vaccines for the entire population and SARS-CoV-2 variants are challenges for pharmaceutical industries. On the contrary, efforts have been made to create different vaccines with different approaches so that they can be used by the entire population. Here, we summarize about 8162 clinical trials, showing a greater number of drug clinical trials in Europe and the United States and less clinical trials in low-income countries. Promising results about the use of new drugs and drug repositioning, monoclonal antibodies, convalescent plasma, and mesenchymal stem cells to control viral infection/replication or the hyper-inflammatory response to the new coronavirus bring hope to treat the disease.