Repurposing candidates for COVID-19 from UCSF, Aldeyra
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A UCSF team has keyed in on more than five dozen compounds against nearly as many targets that could be repurposed to target the virus behind COVID-19.
Meanwhile, a repurposing screen by Aldeyra could yield further antiviral candidates as well as anti-inflammatory therapies to mitigate excessive immune responses against the virus.
The University of California San Francisco's Quantitative Biosciences Institute (QBI) COVID-19 Research Group unveiled Monday, in a preprint posted on bioRxiv, the 69 drug repurposing candidates in preclinical development through FDA approval, against 66 “druggable” human targets, could inhibit SARS-CoV-2.
They did so by expressing in cultured human cells 26 of SARS-CoV-2’s 29 proteins, and determining via in vitro biochemistry assays the human cellular targets with which each viral protein physically interacted.
The authors emphasized that “it is important to note that pharmacological intervention with the agents we identified in this study could be either detrimental or beneficial for infection.” The group is testing the 69 compounds for antiviral activity.
Repurposing candidates include at least two that inhibit BRD2/BRD4: apabetalone (RVX-208) from Resverlogix Corp. (TSX:RVX), which is in Phase III testing for cardiovascular disease, and ABBV-744 from AbbVie Inc. (NYSE:ABBV), which is Phase I testing for cancer. Other compounds identified were Iclusig ponatinib from Takeda Pharmaceutical Co. Ltd. (Tokyo:4502; NYSE:TAK), a lymphoma drug against RIPK1; indomethacin, a non-steroidal anti-inflammatory drug against PTGES2; and chloroquine and several antibiotics with off-target activity against mitochondrial ribosomes.
Separately, Aldeyra Therapeutics Inc. (NASDAQ:ALDX) announced Tuesday plans to screen its library of reactive aldehyde species (RASP) inhibitors, including clinical candidates ADX-629 and reproxalap, for anti-inflammatory and antiviral activity in COVID-19. It has submitted a proposal to Biomedical Advanced Research and Development Authority (BARDA) to develop ADX-629 to treat SARS-CoV-2 infection.
According to the company, ADX-629 and reproxalap are structurally related to chloroquine. Both have reduced inflammation in animal models of cytokine storm, and the company said reproxalap showed “preliminary activity” in a preclinical model of acute respiratory distress syndrome (ARDS). In COVID-19, ARDS is an inflammatory complication and is associated with high mortality.
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BRD2 - Bromodomain containing 2
BRD4 - Bromodomain containing 4
PTGES2 - Prostaglandin E synthase-2
RIPK1 (RIP1) - Receptor-interacting serine-threonine kinase 1