East meets West in COVID-19 therapeutics.

An extensively explored strategy against COVID-19 is drug repurposing, which can be directed against such targets as viral entry, replication, membrane fusion and assembly [1]. In recent COVID-19 target discovery investigations, some novel targets of high drug repurposing potential have been revealed by focusing on the COVID-19 interacting host proteins and infected host cell proteomics [2,3]. In the COVID-19 therapeutics fields, traditional medicines have also been repurposed for COVID-19 treatment as recommended by the National Health Commission of China (NHCC) [4], albeit without clear mechanistic knowledge and little clinical validation. The first multicenter, prospective, randomized controlled trial of a repurposed traditional medicine against COVID-19 has just been reported [5]. Questions arise regarding their scientific basis and, if founded, how the therapeutic mechanisms of this and other NHCC-recommended repurposed traditional medicines might differ from the targets of the COVID-19 therapeutics.

Mechanistic clues of these NHCC-recommended traditional medicines have been investigated by a multi-omics analysis of the targets of potent (≤1μM) activities (henceforth named potent targets), particularly with respect to the clinical gene expression profiles of several inflammation-related diseases [6]. That analysis has indicated that the potent modulations of several inflammation-regulatory targets are possible mechanisms against COVID-19. It has also exposed the dual inflammation inhibitory (pro) and promoting (con) effects of these traditional medicines. The estimated percentages of the patients with the pro and con effects are 16 %–32 % and 7 %–17 % respectively, with the pro effect patients outnumbering the con effect patients by up to 25 %. These indications are consistent with the reported clinical observations. A multicenter, prospective, randomized controlled trial of the repurposed Lianhuaqingwen capsules in 284 COVID-19 patients has revealed that the clinical improvement and cure rates of the treatment group outnumbers the control group by 19.8 % and 12.7 % respectively [5], while the estimated pro effect patients treated by this capsule outnumbers the estimated con effect patients by 25 % [6]. Moreover, the estimated pro-inflammatory effects in 7 %–17 % patients are consistent with the reported pneumonitis and lung injury in the patients of interstitial lung diseases treated by kampo formulations (references in [6]).

Based on this ability in revealing the targets of the traditional medicines against COVID-19 that are consistent with the clinical observations, it is worthwhile to further evaluate the potent targets of the traditional medicines revealed by the multi-omics analysis. There are ∼1−2 dozen potent targets of each of the NHCC-recommended traditional medicines (Supplementary Table S1), some of which are involved in inflammation regulations [6]. If the potent modulations of some of these targets are indeed responsible for the effects of the traditional medicines against COVID-19, some of them are likely identifiable by the two target discovery investigations [2,3], because the involvement of these targets in COVID-19 may be manifested by an interaction with a COVID-19 protein or by elevated expression during COVID-19 infection. To probe this question, we compared the potent targets of eight NHCC-recommended traditional medicines [6] (Supplementary Table S1) with the targets revealed by the two target discovery investigations [2,3].

Significantly, four potent targets of six NHCC-recommended traditional medicines have been identified by the two target discovery investigations, three of which are the targets of clinical trial drugs of repurposing potential (Table 1 ). One target MIF of five traditional medicines is in the top-3 ranked group of a protein cluster elevated by COVID-19 infection [3]. MIF is a critical mediator of macrophage cytokine production and certain innate immune responses in such infections as tuberculosis. There is a phase 2 clinical trial drug (Imalumab) and a preclinical drug (COR100140) targeting MIF for the treatment of cancers and inflammation. Another target DNMT1 of two traditional medicines interacts with COVID-19 ORF8 protein [2], which regulates macrophage inflammation and T-cell development. There are five clinical trial drugs targeting DNMT1 for the treatment of cancers (Oral azacitidine, Guadecitabine, Antroquinonol, Palifosfamide, RX-3117). The third target POLA1 of one traditional medicine is a critical regulator of the type I interferon response, and is targeted by a phase 1 clinical trial drug (HO-221).

Table 1

The common targets of the NHCC-recommended traditional medicines and the two recent target discovery investigations of COVID-19 interacting host proteins and infected host cell proteomics.

Common Target	Target Relationship to COVID-19	Target Regulated Pathways	NHCC-Recommended Traditional Medicines	Targeted Drug in Clinical Trial (Phase)	Drug Original Indications
DNMT1	COVID-19 ORF8 interacting host protein	DNA methylation, Macrophage-mediated inflammatory response	Fangfengtongsheng pill,Angongniuhuang pill	Guadecitabine (3),Antroquinonol (2), Palifosfamide (2), RX-3117 (2), Oral azacitidine (1)	Myelodysplastic syndrome,Acute myeloid leukaemia,Non-small-cell lung cancer,Soft tissue sarcoma,Bladder cancer
POLA1	COVID-19 NSP1 interacting host protein	DNA replication, Type I interferon activation	Qingfeipaidu decoction	HO-221 (1)	Viral infection
MIF	Belong to a cluster of host proteins increased by COVID-19 infection over time	Macrophage inflammatory pathway	Fangfengtongsheng pill, Suhexiang pill, Qingfeipaidu decoction, Jinhuaqinggan granula, Lianhua Qingwen capsules	Imalumab (2)COR100140 (Preclinical)	Colorectal cancer,Inflammation
TUBB3	Belong to a cluster of host proteins increased by COVID-19 infection over time	Neurogenesis, Lymphocyte proliferation, Pathogenic Escherichia coli infection	Fangfengtongsheng pill,Angongniuhuang pill,Qingfeipaidu decoction,Jinhuaqinggan granula

The shared targets of the repurposed traditional medicines and of the clinical trial drugs identified by the established target discovery methods [2,3] suggest the possible existence of common inflammation-regulatory mechanisms against COVID-19 by both conventional drugs and traditional medicines. The identification of these common mechanisms by the target discovery methods [2,3] and multi-omics analysis [6] not only provide the clues for repurposing drugs and traditional medicines against COVID-19, but also exhibit the potential utilities of these methods for broader applications in the repurposing of drugs and traditional medicines against various other disease conditions that need effective treatments.

Declaration of Competing Interest

There are no conflicts to declare.