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Summary of 10 Approved COVID-19 Small Molecule Drugs

Release time:2023/1/9 16:48:05
Author:Huateng Pharma

So far, the need for effective therapies for COVID-19 remains high. As peoples understanding of the structure, function a…

Corona Virus Disease 2019 (COVID-19), a disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has had a devastating impact on the world's population and is the most serious global health crisis since the 1918 influenza pandemic. Since being declared a global pandemic by WHO on 11 March 2020, the virus has continued to threaten the health of people worldwide.


The COVID-19 outbreak has become a global crisis that has killed more than 6 million people worldwide. It wreaks havoc on societies and economies, and so far, the need for effective therapies for COVID-19 remains high. As people's understanding of the structure, function and pathogenic processes of the novel coronavirus has improved, many small molecule drugs with potential to fight COVID-19 have been developed.

COVID-19 is caused by SARS-CoV-2. SARS-CoV-2 is a beta coronavirus with a positive-sense single-stranded RNA genome containing 14 open reading frames (ORFs). Two ORFs encode the polymerins PP1a and PP1b. The four ORFs encode a series of structural proteins, including spike protein (S), membrane protein (M), envelope protein (E), and nucleocapsid protein (N). The S protein recognizes human ACE2 receptors and is cleaved by host proteases, responsible for viral binding and entry into host cells. Mpro (major proteases) and PLpro(papain like proteases) are essential for the production and function of non-structural proteins (NSPs).  

SARS-CoV-2 genome and its structure diagram.jpg

SARS-CoV-2 genome and its structure diagram

The genome size of SARS-CoV-2 is close to 30 kb. It contains 14 open reading frames (ORFs) and encodes 29 proteins. Two of these ORFs, accounting for about two-thirds of the genome, encode two polymeric proteins, which are hydrolyzed by the M protease (Mpro) and papain like protease (PLpro) into 16 non-structural proteins (nsps). (Source: Reference 2)

After the novel coronavirus invades cells, it begins to replicate in large quantities; and the virus's RNA-dependent RNA polymerase (RdRp, also known as nsp12) plays a vital role in the synthesis of the virus's genetic material, RNA. With RNA polymerase as the core, the virus will cleverly use other cofactors (such as nsp7/nsp8, etc.) to assemble an efficient RNA synthesis machine for self-replication. As the core component of this replication machine, RNA polymerase is one of the most important antiviral drug targets. Destroying the function of this core device can prevent the replication of the virus and finally achieve the purpose of treatment. Therefore, targeting these functional proteins is a reasonable strategy to inhibit infection and replication of COVID-19.

 Life cycle of SARS-CoV-2.jpg

Life cycle of SARS-CoV-2

The SARS-CoV-2 S protein recognizes the ACE2 receptor and is simultaneously cleaved by host proteases and enters the target cell, then the gRNA is released and translated into pp1a and pplb, which are hydrolyzed into NSPs necessary for viral replication. Catalyzed by RdRp, new gRNAs are generated and encode structural proteins to assemble progeny viruses. (Source: Reference 2)

Compared with biological products such as monoclonal antibodies and plasma products, small molecules are more flexible in binding to target molecules when acting as antagonists or agonists. Their lower production costs and higher stability also make them ideal therapeutic agents for clinical and research applications. With the increasing understanding of the pathogenic mechanism of SARS-CoV-2 infection, small molecules from natural sources or through chemical synthesis have shown their great therapeutic potential by interfering with various pathways. The development of small molecules for the treatment of COVID-19 has been achieved through multiple strategies, including computer-aided lead compound design and screening, natural product discovery, drug reuse, and combination therapies.

According to incomplete statistics, so far, 10 small-molecule COVID-19 therapeutic drugs have been approved or authorized globally.

10 small-molecule COVID-19 drugs.png 

Small-molecule COVID-19 therapeutics have demonstrated their great potential in the development of anti-COVID-9 therapies. However, the current understanding of SARS-CoV-2 and COVID-9 is only the tip of the iceberg, and it is necessary to improve the understanding of SARS-CoV- 2 and a deeper understanding of its life cycle. It is also necessary to characterize the viral components involved in its pathological process, and further elucidate the detailed mechanism of virus replication and interaction with host cells in order to better understand the virus' destruction of the host immune system mechanism, so as to find drugs that are well targeted and more effective.

Several worrisome variants such as Alpha (B.1.1.7), Delta (B.1.617.2), and Omicron (B.1.1.529) pose ongoing challenges to the drug development industry, and resistance caused by viral mutations drives scientists continuing to search for new compounds, targets, and drug combination strategies. More targeted antiviral drugs are the urgent needs of hospitalized patients with severe symptoms. The elderly over 65 years of age and vulnerable people with underlying diseases are still the most deserving of special attention, and drug development needs special attention.

Huateng Pharma is a world leading supplier dedicated to providing pharmaceutical intermediates and PEG derivatives to customers worldwide. We can provide custom synthesis for commercial scaleup of COVID-19 oral drug Ensitrelvir (S-217622) and Paxlovid intermediates. We can also supply mPEG-DTA (ALC-0159), mPEG-DSPE, mPEG-DMG and other PEG products which used as excipients in COVID-19 vaccines.

Paxlovid Intermediates

CAS NO.67911-21-1   Caronic anhydride
CAS NO.194421-56-2    6,6-Dimethyl-3-Azabicyclo[3.1.0]hexane-2,4-dione
CAS NO.565456-77-1    (1R,2S,5S)-Methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride
CAS NO.943516-54-9 

CAS NO.72748-35-7       Lambda-cyhalothric acid

Ensitrelvir (S-217622) Intermediates

CAS NO.:1360105-53-8   3-Tert-butyl-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dione

CAS NO.:1893125-36-4   6-Chloro-2-methyl-2H-indazol-5-amine

CAS NO.:135206-76-7     3-(Chloromethyl)-1-methyl-1H-1,2,4-triazole

CAS NO.:157911-56-3     2,4,5-Trifluorobenzyl bromide

CAS NO.:76-05-1             Trifluoroacetic acid



[2].Lei, S., Chen, X., Wu, J. et al. Small molecules in the treatment of COVID-19. Sig Transduct Target Ther 7, 387 (2022). https://doi.org/10.1038/s41392-022-01249-8



[6] https://www.cnki.com.cn/Article/CJFDTotal-GRKZ202012017.htm

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