Types of Specific Inhibitors
Agents
Therapeutic targets & Mechanisms
Notes
Specific Mpro (3CLpro or NSP5) inhibitors PLpro  inhibitors Exonuclease inhibitors (EI) Nucleotide inhibitors (NI) (selective RdRp inhibitors) 4’-modified nucleoside drug candidates Small molecular compound PAXLOVID= Nirmatrelvir (PF-07321332, NMV) + Ritonavir (as a pharmacokinetic enhancer) 9,10-dihydrophenanthrenes peptidomimetic YH-53 (compounds) GC376, boceprevir, calpain inhibitors II, and XII, Chloroquine (CQ) & Hydroxychloroquine (HCQ), peptide inhibitors and GRL0617 Pibrentasvir & Ombitasvir Remdesivir, Sofosbuvir, Lopinavir, Favipiravir, Molnupiravir & AT-527 FNC (azvudine) islatravir balapiravir Inhibit the viral target Mpro, an orally administrated inhibition of viral replication and its survival in the host cell, a potent and selective inhibitor of the SARS-CoV-2 main protease (Mpro), lack of genetic toxicity. Inhibit the viral target PLpro, regulate viral replication; dysregulates host immune sensing by viral polypeptide cleavage, de-ISGlyation and immune suppression. Inhibit the viral target RdRp. Oct 2020, the US FDA approved remdesivir as the first drug for the treatment of Covid-19 better therapeutic efficacy than remdesivir. main protease (3C-Like protease), covalent inhibitors of 3CLpro, a better selectivity index than remdesivir, no clinically relevant risks associated with PAXLOVID administration. Papain-like protease broad-spectrum prodrugs Due to CV adverse drug reactions (CV-ADRs), need adequate CV monitoring
Specific inhibitors of RdRp and Nsp15/EndoU, and others Alectinib Naldemedine & Ergotamine Stapled peptides for RdRp for NSP15 mimic Helix 1 of the human ACE2 receptor other several kinases including CMGC, CK2, CDK, PKC, PIKFYVE, and EIF2AK2
Various signaling pathways including MAPK, GFR signaling, TGF-β, autophagy, and AKT.
Specific anti- hepatitis C virus (HCV) drugs Anti-HIV drugs neoechinulin B (1a) N3G, a mimetic of the HIV-1 gp41 HR1 trimer anti-HIV-drug-vitamin c derivatives cocktails inactivating the liver X receptors (LXRs), antiviral activities against HCV & SARS-CoV-2 Inhibit infection of HIV-1 & human β-coronaviruses by blocking the hexameric structure formation a prenylated indole diketopiperazine alkaloid β-coronaviruses (MERS-CoV, HCoV-OC43 & SARS-CoV-2)
Antimalarial drugs
Mefloquine chloroquine (CQ)/ hydroxychloroquine (HCQ) inhibit SARS-CoV-2 replication & reduce SARS-CoV-2 entry against SARS-CoV-2 PLpro
An orally available host-acting agent
Adjunctive treatment
Melatonin (a low dose), 9 mg daily, orally for 14 days. Methylprednisolone (MP) Chitosan and its derivatives its anti-oxidation, anti-inflammation by inflammasome activation, and improvements of immune and clinical symptoms. reduce inflammation reaction and tissue damage direct antiviral activity as vaccine adjuvants reduce the levels of TNF-α, IL-1β cytokines, MDA, and NO levels, and significantly increase SOD level. bradycardia on the premise of the long-term use of arbidol
Nanotechnology (Nanomaterials) personal protective equipment anti-viral nano-coats, nano-based vaccines nanomaterial-based point-of-care devices agents carriers gene editing agents therapeutic agents ZnO nanoparticles based on modifiable engineering materials and useful physicochemical properties, nanobubble ozonated hyaluronic acid-decorated liposomal (NOHAL) solution possible unintended immunotoxicity, through the nose and/or oral cavity. ZnONPs
Botanical Drugs or medicinal plants plant chemicals: Artemisia annua L. Angeloylgomisin O Schisandrin B Vitex negundo L. (VNL) Kabasura kudineer Nilavembu kudineer phytomedicine-based therapies, effectively inhibit SARS-CoV-2 entry adjuvant therapeutic agent & a single source of a cocktail of Mpro inhibitors the two most widely approved formulations to treat COVID-19.
Lower side effects, combination with remdesivir
MNPs
Gallinamide A Seaweed’s bioactive compounds Microalgal metabolites (carotenoids and lipids) directly interacted with cathepsin L in cells can inhibit the omicron variant anti-inflammatory properties
broad-spectrum target inhibition by marine natural products
TCM or Herbal medicine Jinzhen granule (JZ) (gallic acid 1.97 mg/g, baicalin 20.69 mg/g, glycyrrhizic acid 4.92 mg/g, hyodeoxycholic acid 4.86 mg/g, cholic acid 4.07 mg/g) A combination of Huoxiang Zhengqi Oral Liquid and Jinhao Jiere Granules Baidu Jieduan granules Bufei Huoxue (BFHX) Jinhua Qinggan granule (JHQG) Keguan-1 Lianhua Qingwen (LHQW) Maxingshigan-Weijing decoction (MWD) Reduning injection Reyanning mixture Shenhuang granule Shufeng Jiedu capsule (SFJDC)* Xiyanping (XYP) injection Plant secondary metabolites or herbal bioactives (e.g., Green tea extract) antiviral activity by inhibition of main protease and endoribonuclease (NSP15), regulating the NF-κB/MAPK pathway and the mitochondria-mediated apoptotic pathway. antiviral, anti-inflammatory, and immunoregulatory activities in acute lung injury, reduce the use of antibiotics and glucocorticoids, improve LPS-induced ALI by reducing inflammation and pulmonary vascular endothelial injury, safe and effective for patients with mild to moderate COVID-19, especially when combined with conventional western medicine. An alternative treatment Huoxiang Zhengqi Oral Liquid: oral before meals, 10 mL/time, 2 times/day, a course of 5 days. Jinhao Jiere Granules: dissolve in boiling water and take after meals, 8 g/time, 2 times/day, a course of 5 days, followed up for 14 days, respectively. *A patented herbal drug composed of eight medicinal plants.
Macrolide antimicrobial agents
Clarithromycin Azithromycin
An immunomodulating drug and suppresses cytokine storms in viral respiratory diseases (including influenza)
Monotherapy or combination, but may induce QT long and malignant arrhythmias
Others: Multi-targeted anti-viral drugs Combinations in Covid-19 management three alkaloids (lycorine, emetine, and cephaeline) Such as iota carrageenan nasal spray, ermectin oral drops, omega-3 supplementation, and a quadruple treatment of zinc, quercetin, bromelain, and vitamin C. inhibitors of viral entry The comprehensive effects of logical combinations with different mechanisms of action.
target N-terminal domain (NTD) of nucleocapsid protein (NPro) to inhibit the replication