Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis ), leflunomide was found to target pathways enriched in COVID-19. In vitro , both leflunomide (EC50 41.49±8.8μmol/L) and teriflunomide (EC50 26μmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.

Traditional Indian medical practices (Ayurveda, Siddha, Unani, and homeopathy) are a vast reservoir of knowledge about medicinal plants. The promising pharmacological properties of these plants have paved the way for developing therapy against novel Coronavirus (CoV) infection. The current review will summarize published works of literature on the effects of traditional Indian medicinal plants against acute respiratory infection (COVID‐19, SARS, Influenza, and Respiratory syncytial virus infection) and registered clinical trials of traditional Indian herbal medicines in COVID‐19. The current study aims to comprehensively evaluate the data of traditional Indian medicinal plants to warrant their use in COVID‐19 management. PubMed, Embase, and Cochrane databases were searched along with different clinical trial databases. A total of 22 relevant traditional Indian medicinal plants (35 relevant studies) were included in the current study having potential antiviral properties against virus‐induced respiratory illness along with promising immunomodulatory and thrombolytic properties. Further, 36 randomized and nonrandomized registered clinical trials were also included that were aimed at evaluating the efficacy of herbal plants or their formulations in COVID‐19 management. The antiviral, immunomodulatory, and thrombolytic activities of the traditional Indian medicinal plants laid down a strong rationale for their use in developing therapies against SARS‐CoV‐2 infection. The study identified some important potential traditional Indian medicinal herbs such as Ocimum tenuiflorum, Tinospora cordifolia, Achyranthes bidentata, Cinnamomum cassia, Cydonia oblonga, Embelin ribes, Justicia adhatoda, Momordica charantia, Withania somnifera, Zingiber officinale, Camphor, and Kabusura kudineer, which could be used in therapeutic strategies against SARS‐CoV‐2 infection.

Terpenoids such as geraniol and citral are known to have antibacterial, antifungal and anti-cancerous properties; however, their mechanism of action is least understood. In this study, the antifungal mechanism of monoterpene alcohol (geraniol) and monoterpene aldehyde (citral) was studied using Saccharomyces cerevisiae throughout 120 h duration and over a maximum tolerable dosage of 0.5% (v/v). Cell growth studies using optical density readings at 600 nm (OD λ=600 nm), Cell viability using MTT assay, Na + /K + leakage into media, osmotic stress using flame photometry, detection of metabolites like dehydroergosterol (DHE), H 2 O 2 using fluorescence spectroscopy, changes in functional group analysis using FT-IR, elemental analysis using EDAX, DNA damage using gel electrophoresis and cellular structural changes using SEM were carried out. Growth inhibition studies using OD λ=600 nm and MTT assays suggest that both geraniol and citral inhibited the growth kinetics significantly up to 0.1% v/v at and significantly increased beyond 0.1% at all the studied time points. Both the monoterpenoids induced the osmotic stress in S. cerevisiae measured as a change in reduction in pH, [H] + concentration, with elevation in [Na] + and [K] + leakage into the media. Geraniol treatment reduced the levels of metabolites, dehydroergosterol (DHE) and H 2 O 2 , in a time-dependent manner whereas citral only affected their levels at 120 h. Energy dispersive X ˗ ray spectroscopy (EDAX) studies suggest that both the monoterpenoids treatment differentially modulated the cellular elemental contents. Geraniol (0.03% v/v) and not the citral treatment induced DNA damage. Cellular structural analysis showed that both monoterpenoids have differential damaging effects to S. cerevisiae. This study shows that having an aldehyde and alcohol group on the terpenoids strongly affect the anti-fungal activity.

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