Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 May:179:106201.
doi: 10.1016/j.phrs.2022.106201. Epub 2022 Apr 1.

COVID-19 and the promise of small molecule therapeutics: Are there lessons to be learnt?

Wei Shen Ho  1 , Ruirui Zhang  1 , Yeong Lan Tan  1 , Christina Li Lin Chai  2
Affiliations
Review

COVID-19 and the promise of small molecule therapeutics: Are there lessons to be learnt?

Wei Shen Ho et al. Pharmacol Res. 2022 May.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic had grounded the world to a standstill. As the disease continues to rage two years on, it is apparent that effective therapeutics are critical for a successful endemic living with COVID-19. A dearth in suitable antivirals has prompted researchers and healthcare professionals to investigate existing and developmental drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although some of these drugs initially appeared to be promising for the treatment of COVID-19, they were ultimately found to be ineffective. In this review, we provide a retrospective analysis on the merits and limitations of some of these drugs that were tested against SARS-CoV-2 as well as those used for adjuvant therapy. While many of these drugs are no longer part of our arsenal for the treatment of COVID-19, important lessons can be learnt. The recent inclusion of molnupiravir and Paxlovid™ as treatment options for COVID-19 represent our best hope to date for endemic living with COVID-19. Our viewpoints on these two drugs and their prospects as current and future antiviral agents will also be provided.

Keywords: Antivirals; Baricitinib (PubChem CID: 44205240); COVID-19; Chloroquine (PubChem CID: 2719); Dexamethasone (PubChem CID: 5743); Drug discovery; Hydroxychloroquine (PubChem CID: 3652); Ivermectin (PubChem CID: 6321424); Lopinavir (PubChem CID: 92727); Molnupiravir (Pubchem CID: 145996610); Nirmatrelvir (PubChem CID: 155903259); Remdesivir (PubChem CID: 121304016); Ritonavir (PubChem CID: 392622); Small molecule therapeutics.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

ga1
Graphical abstract
Fig. 1
Fig. 1
Chemical structures of the most promising drug candidates for the treatment of COVID-19. Some of these compounds are being explored as combination drugs.
Fig. 2
Fig. 2
(A) Life cycle of SARS-CoV-2. The key steps are highlighted, and drugs that were proposed to inhibit those steps are indicated where appropriate. (B) Pathophysiology of COVID-19. In most cases, viral infection is limited to the URT, and the patient recovers within 14 days with no further complications. However, the viral infection can migrate to the LRT and lead to ARDS or a cytokine storm. This has been proposed as the main cause of death from COVID-19-related complications.
Fig. 3
Fig. 3
(A) Metabolism of prodrug remdesivir (GS-5734) to GS-441524 monophosphate, which is phosphorylated in host cells to the bioactive triphosphate of GS-441524 (GS-443902). (B) When GS-441524 (represented in purple) is incorporated into the replication strand (represented in grey), the machinery stalls while trying to incorporate the 4th nucleotide due to steric clashes between the 1’-CN group of GS-441524 and the polymerase, resulting in its delayed chain termination mechanism of action.
Fig. 4
Fig. 4
Avermectin and its semi-synthetic derivative ivermectin. Highlighted parts denote the structural difference between the two compounds.
Fig. 5
Fig. 5
The metabolite of Molnupiravir, NHC (represented in green) is a primary mimetic for cytidine, pairing with guanidine during viral replication. Tautomerism of NHC can allow it to occasionally mimic uridine, thus pairing with adenosine. When the NHC-containing strand is used as a template for further replication, adenosine or guanidine may be paired with NHC, thereby inducing mutagenesis.
Fig. 6
Fig. 6
Structure of peptidomimetic Nirmatrelvir. P4 to P1 denotes the positions of the sequence from the N-terminus to the C-terminus.
Fig. 7
Fig. 7
Effective treatment options against COVID-19 thus far and the phases of SARS-CoV-2 pathophysiology for which they act on.
See this image and copyright information in PMC

References

    1. Khandia R., Singhal S., Alqahtani T., Kamal M.A., El-Shall N.A., Nainu F., Desingu P.A., Dhama K. Emergence of SARS-CoV-2 Omicron (B.1.1.529) variant, salient features, high global health concerns and strategies to counter it amid ongoing COVID-19 pandemic. Environ. Res. 2022;209 - PMC - PubMed
    1. Yu Y.B., Briggs K.T., Taraban M.B., Brinson R.G., Marino J.P. Grand challenges in pharmaceutical research series: ridding the cold chain for biologics. Pharm. Res. 2021;38(1):3–7. - PMC - PubMed
    1. Naveja J.J., Madariaga-Mazon A., Flores-Murrieta F., Granados-Montiel J., Maradiaga-Cecena M., Alaniz V.D., Maldonado-Rodriguez M., Garcia-Morales J., Senosiain-Pelaez J.P., Martinez-Mayorga K. Union is strength: antiviral and anti-inflammatory drugs for COVID-19. Drug Discov. Today. 2021;26(1):229–239. - PMC - PubMed
    1. Tarighi P., Eftekhari S., Chizari M., Sabernavaei M., Jafari D., Mirzabeigi P. A review of potential suggested drugs for coronavirus disease (COVID-19) treatment. Eur. J. Pharmacol. 2021;895 - PMC - PubMed
    1. Li D., Hu J., Li D., Yang W., Yin S.F., Qiu R. Reviews on biological activity, clinical trial and synthesis progress of small molecules for the treatment of COVID-19. Top. Curr. Chem. 2021;379(1):52. - PMC - PubMed

Publication types

Substances