Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials

Abstract

The ongoing pandemic of coronavirus disease-2019 (COVID-19) is being caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease continues to present significant challenges to the health care systems around the world. This is primarily because of the lack of vaccines to protect against the infection and the lack of highly effective therapeutics to prevent and/or treat the illness. Nevertheless, researchers have swiftly responded to the pandemic by advancing old and new potential therapeutics into clinical trials. In this review, we summarize potential anti-COVID-19 therapeutics that block the early stage of the viral life cycle. The review presents the structures, mechanisms, and reported results of clinical trials of potential therapeutics that have been listed in clinicaltrials.gov. Given the fact that some of these therapeutics are multi-acting molecules, other relevant mechanisms will also be described. The reviewed therapeutics include small molecules and macromolecules of sulfated polysaccharides, polypeptides, and monoclonal antibodies. The potential therapeutics target viral and/or host proteins or processes that facilitate the early stage of the viral infection. Frequent targets are the viral spike protein, the host angiotensin converting enzyme 2, the host transmembrane protease serine 2, and clathrin-mediated endocytosis process. Overall, the review aims at presenting update-to-date details, so as to enhance awareness of potential therapeutics, and thus, to catalyze their appropriate use in combating the pandemic.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; coronavirus; endocytosis; spike protein; viral entry; viral fusion.

Figure 1

A representation of the viral particle of SARS-CoV-2 depicting the structural proteins: spike (S) protein, envelope (E) protein, membrane (M) protein, and nucleocapsid (N) protein. It also shows the early stage of the life cycle of the virus which starts by the spike S protein binding to the host cell ACE2, which is followed by viral entry. The viral entry takes place either by (a) endocytosis or (b) direct fusion. In endocytosis-mediated entry, the spike S protein activation appears to take place in endosomes by the action of furin. Further proteolysis and subsequent fusion occur because of the action of cathepsin L in endo-lysosomes. In direct fusion entry, the process is mediated by TMPRSS2 and/or furin; however, other trypsin-like proteases may also contribute. Either way, the RNA genetic material of the virus is released, and the late stage of the life cycle subsequently takes place by RNA replication, viral protein synthesis, maturation, assembly, and release of the new virus.

Figure 2

The chemical structures of quinoline-based antimalarial drugs that are being tested in COVID-19 patients.

Figure 3

The chemical structures of RAAS modifiers. (A) The chemical structures of ACEIs and (B) The chemical structures of ARBs that are being tested with relevance to COVID-19.

Figure 4

The chemical structures of HMG CoA reductase inhibitors being tested in clinical trials for potential therapeutic benefits in COVID-19 patients.

Figure 5

The chemical structures of TMPRSS2 inhibitors that are being tested in clinical trials for COVID-19 patients. The listed drugs potentially prevent the viral fusion with the host cell.

Figure 6

The chemical structure of umifenovir (abidol), an antiviral drug with multiple antiviral mechanisms of action. The drug is being tested alone or in combination with other potential therapeutics for the treatment of COVID-19 patients.

Figure 7

The chemical structures of three macrolides that are currently being evaluated in clinical trials for the treatment of COVID-19 patients. The macrolides also exhibit anti-inflammatory/ immunomodulatory effects.

Figure 8

The chemical structures of a broad-spectrum antiparasitic agent (ivermectin), an aryl nitro-based antiparasitic agent (niclosamide), and a broad-spectrum antibacterial agent (doxycycline). Doxycycline also exhibits potential anti-inflammatory effects.

Figure 9

The chemical structures of alkylamine-based drugs that are currently being tested in COVID-19 patients. Presented are the antipsychotic phenothiazine chlorpromazine, the antiarrhythmic benzofuran-based amiodarone, the phenylalkylamine-based calcium channel blocker of verapamil, and the trans-stereoisomer of 4-(aminomethyl)cyclohexane-carboxylic acid antifibrinolytic agent, also known as tranexamic acid.

Figure 10

The chemical structures of miscellaneous agents that are also being tested in clinical trials for COVID-19 patients and exhibit inhibitory effects on the early events of the viral life cycle. Important among them are the steroid-based potassium sparing diuretic spironolactone, which has been shown to block the host androgen receptors, and thus, to decrease the transcription of TMPRSS2 gene. Linagliptin is dihydro-purinedione-based inhibitor of DPP-4, a functional receptor for the spike protein of MERS-CoV, and a potential receptor for SARS-CoV-2. It also exhibits therapeutically beneficial anti-inflammatory effects.

Figure 11

The chemical structures of pyrrolo-pyrimidine-based JAK inhibitors. The drugs potentially block clathrin-mediated endocytosis of the virus. They also exhibit anti-inflammatory/immune-modulatory agents.

Figure 12

A representative chemical structure of UFH and LMWHs. These sulfated glycosaminoglycans exhibit remarkable antithrombin-mediated anticoagulant activity and anti-inflammatory and antiviral effects.