Drug repurposing study reveals potential therapies for COVID-19
As Hong Kong battles with a third wave of the coronavirus disease 2019 (COVID-19) outbreak, researchers from the University of Hong Kong (HKU) and several institutions in the US have identified 13 drugs at clinical stage or approved by the US FDA that may effectively inhibit replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The researchers performed high-throughput screening and repositioning analysis using the ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) library of approximately 12,000 drugs that have been approved by the US FDA or registered outside the US, entered clinical trials, or undergone significant preclinical characterization. [Nature 2020, doi: 10.1038/s41586-020-2577-1]
Thirteen compounds, including the PIKfyve kinase inhibitor, apilimod, and the cysteine protease inhibitors, MDL-28170, Z LVG CHN2, VBY-825 and ONO-5334, were found to harbour effective concentrations (EC50S <500 nM) in at least one human cell line, suggesting that they could inhibit SARS-CoV-2 replication at doses that may be achievable in vivo.
Notably, apilimod, MDL-28170 and ONO-5334 were found to antagonize viral replication in human induced pluripotent stem cell (iPSC)–derived pneumocyte-like cells. “Treatment with ONO-5334 and MDL-28170 reduced the number of infected cells by 72 percent and 65 percent, respectively, while apilimod blocked SARS-CoV-2 challenge by 85 percent,” the researchers reported.
Furthermore, apilimod was found to potently antagonize SARS-CoV-2 replication in a primary human lung explant model.
Apilimod was previously evaluated in phase II clinical trials on Crohn’s disease, rheumatoid arthritis, and common variable immunodeficiency, as well as in phase I studies on follicular lymphoma. In humans, doses of ≤125 mg BID with a Cmax of 0.265 +/- 0.183 mM were tell tolerated with a desirable safety profile, suggesting that therapeutic dosing may be achieved in patients at concentrations likely to promote antiviral activity. [PLoS One 2018;13:e0204532; IDrugs 2007;10:53-59; J Cell Biochem 2020;121:2927-2937; Blood 2017;129:1768-1778]
“Interestingly, apilimod also efficiently inhibits Ebola virus, Lassa virus and Marburg virus in human cell lines, underscoring its potential broad-spectrum antiviral activity,” the researchers wrote. [PLoS Negl Trop Dis 2017;11:e0005540; Chem Biol 2013;20:912-921]
MDL-28170 was previously shown to impair infection by SARS-CoV-1 and Ebola virus, while Z LVG CHN2 was shown to suppress herpes simplex virus replication. [J Virol 2012;86:10112-10122; Expert Rev Anti Infect Ther 2012;10:1129-1138; J Virol 2990;64:941-943]
“Importantly, ONO-5334 was well tolerated in phase II clinical trials on osteoporosis, but its development was discontinued due to an unfavourable competitive landscape,” the researchers highlighted. [J Bone Miner Res 2011;26:1303-1312; J Bone Miner Res 2014;29:458-466]
According to the researchers, repurposing of clinically evaluated drugs represents one of the most practicable strategies to accelerate the deployment of novel therapies for COVID-19, given that development of a SARS-CoV-2 vaccine will likely take 12–18 months, while development of a novel antiviral therapeutic can take 10–17 years. “Repurposing of the HIV-1 protease inhibitors, lopinavir-ritonavir, the hepatitis C virus protease inhibitor, danoprevir, and the influenza antiviral, favipiravir, has been the focus of clinical investigation,” they noted.In another study, researchers from the Columbia University, New York, US, and the HKU identified several potent neutralizing monoclonal antibodies (mAbs) directed to multiple epitopes on SARS-CoV-2 spike, which represent promising candidates for clinical development as potential therapeutic and/or prophylactic agents. Nine of these mAbs exhibited IC50 of 0.7–9 ng/mL. [Nature 2020, doi: 10.1038/s41586-020-2571-7]