Drug Reprofiling: A Prospective Approach to Battle Chronic Ailments

Repurposing Existing Antifungal and Antiviral Drugs

A scientific prospection of the repurposed antiviral and antifungal medications from 2012 to 2022 was made and the results are represented in Fig. 5. A total of 768 publications on drug repurposing of antiviral drugs resulted. In the same period, antifungal drugs were repurposed for many applications and the results were summarized in 410 publications. Starting with 2012, there were only six publications related to the repurposing of antiviral and antifungal drugs. However, the numbers have drastically increased since 2015. The number of publications with regard to the repurposing of antifungal drugs has exceeded 50 and it reached a maximum of 75 in the year 2021. The year 2022 has already witnessed the publication of 56 manuscripts and the number is likely to cross 100 by the end of the year. But the trend is quite interesting in the case of antiviral drugs. The total number of manuscripts on repurposing from 2012 to 2019 is only 117. After 2019, there is a rise in publications with the number being 252 in 2020, 292 in 2021, and 107 in 2022.

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Fig. 5 Top Cooperative Patent Categorization (CPC) classification codes with heat map.

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Based on the review of literature, here are some scientific hypotheses of drug repurposing, in terms of their modes of action, to a point of effective therapeutic indications.

• ➢ Despite the fact that colorectal cancer (CRC) is one of the most commonly diagnosed cancer worldwide, effective therapy is still challenging to attain. According to Shi et al, oxiconazole (OXI), a broad-spectrum antifungal drug, has some antitumor properties when applied to CRC. OXI-induced growth reduction of CRC cells is characterized by autophagy arrest and subsequent apoptosis as key processes. By deactivating the Akt/mTOR pathway and preventing RAB7A-mediated autophagosome-lysosome fusion, OXI initiates autophagy by lowering the protein levels of peroxiredoxin-2 (PRDX2), an antioxidant enzyme for reactive oxygen species (ROS) detoxication. This results in an extreme accumulation of autophagosomes and subsequently suppresses the growth of CRC cells. Overexpressing PRDX2 or interfering with autophagy consistently makes it harder for CRC cells to stop their proliferation as a result of OXI. Additionally, OXI combined oxaliplatin, a cornerstone medication for the treatment of CRC, achieves a better antitumor effect. Together, our results offer unique mechanistic insights into the mechanisms behind OXI-induced autophagy stoppage and the growth inhibitory effect on CRC cells, and they point to a potentially effective therapeutic role for OXI in the management of CRC.¹⁷

• ➢ The highest death rate among carcinomas is present in pancreatic ductal adenocarcinoma (PDAC). Elevated autophagy is necessary for the pathogenesis of PDAC, and hydroxychloroquine has shown promise in preventing it. However, due to its imprecise application and unexpected toxicity, current realization is hampered. A quick and convenient strategy is to look for novel autophagy-modulating therapeutics among already-approved medications. Weng et al undertook a comparative analysis of the treatment responses of different antimalarial/fungal/parasitic/viral medicines in this study utilizing a patient-derived organoid model, and econazole (ECON), an antifungal drug, emerged as the top contender. This action was confirmed by additional testing in cell-line and xenograft models of PDAC and was a direct result of impaired autophagy. More specifically, ECON inhibited lysosome biogenesis while increasing autophagy start. This autophagic stimulation, according to RNA sequencing research, was predominantly caused by altered expression of activation transcription factor 3 (ATF3). In PDAC cells, increased nuclear import of ATF3 and its transcriptional suppression of inhibitor of differentiation-1 (ID-1) resulted in the inactivation of the Akt/mTOR pathway, which in turn caused autophagosome accumulation. The level of the autophagosome rise was enough to trigger ER stress-mediated apoptosis. Additionally, trametinib and ECON's synergistic effects on PDAC. ECON is an autophagy inhibitor. The therapeutic effectiveness of ECON in the treatment of PDAC is directly demonstrated in this study's preclinical and experimental data, and it is also revealed how ECON slows PDAC growth.²⁰

• ➢ Imatinib and a nontoxic dose of ketoconazole (10 M) were used to overcome drug resistance. These drugs also reduced P-gp overexpression and its efflux function, boosting the intracellular accumulation of doxorubicin, and caused higher levels of cell death in chronic myeloid leukemia (CML) cells. Imatinib resistance in CML cells is significantly influenced by P-gp. By concentrating on P-gp-related pathways, ketoconazole was able to overcome the imatinib resistance of CML cells. Patients who are resistant to imatinib would probably benefit from the repurposing of ketoconazole for CML treatment.²¹²²

• ➢ Disulfiram (Antabuse) has been repurposed as an antibacterial drug, and Custodio et al examined the preclinical and clinical research. As an anti-methicillin-resistant Staphylococcus aureus agent, carbapenamase inhibitor, antifungal drug for candidiasis, and treatment for parasitic diseases caused by protozoa (such as giardiasis, leishmaniasis, and malaria) and helminthes (such as schistosomiasis, trichuriasis), preclinical research on the alcohol sobriety aid has been covered.²³

• ➢ Disulfiram has also been shown to be effective as a COVID-19 infection treatment, an HIV latency reversal medication, and a post-Lyme disease syndrome therapy method. In many tropical locations of the world, leishmaniasis continues to be a severe public health issue. Leishmaniasis has the second-highest fatality rate among neglected tropical illnesses, right behind malaria. There are toxic side effects to every therapy currently on the market, and resistance is rising quickly. Drug discovery pipelines using both in-silico and in-vitro techniques were established to identify current medications with antileishmanial activity and anticipate the mechanism of action. Lansoprazole and Posaconazole were shown to be the two most promising active molecules after first screening. Several sites were used to identify potential Lansoprazole and Posaconazole medication targets for Leishmania. Posaconazole and Lansoprazole are two new antileishmanial medications that have previously received FDA approval for use in various conditions, and they both put forth plausible mechanisms of action for their antileishmanial effectiveness.²⁴

• ➢ Due to their high mortality rates and multidrug resistance (MDR), Klebsiella pneumoniae poses a hazard to healthcare globally. DeSarno et al investigated the possibility of treating resistant K. pneumoniae strains by combining zidovudine (AZT) and an already-approved antibiotic.

• ➢ The NDM-1 or KPC-3 carbapenemase was produced by the pneumoniae strains used. By assessing larval mortality and bacterial load, the efficacy of AZT and meropenem combinations was contrasted with that of monotherapies against infections in Galleria mellonella larvae. Checkerboard and time-kill assays were used to determine the impact of the same combinations in vitro. Meropenem-resistant pneumoniae strains were responsive to AZT but resistant to meropenem. In G. mellonella infections, therapy with either AZT and meropenem or meropenem alone had only a modest therapeutic effect. As opposed to monotherapies, combination therapy using meropenem and AZT had significantly higher efficacy. This was associated with suppression but not the eradication of bacterial growth within the larvae. Checkerboard tests revealed an indifferent rather than a synergistic relationship between AZT and meropenem. In conclusion, AZT and meropenem combination therapy is a viable treatment for MDR K. pneumoniae strains that produce carbapenemase.²⁵

• ➢ PI3K/Akt/mTOR pathway is a crucial target in the fight against cancer. De novo drug development takes years, though, and is frequently slowed down by decreased activity and/or unanticipated toxicity in clinical trials. Testing medications that have previously received approval for use in other conditions is one method of accelerating the discovery of new cancer medicines. The FDA-approved HIV-1 protease inhibitor nelfinavir, which is consumed orally to treat HIV/AIDS, has been shown by researchers to lessen endogenous. However, nelfinavir is profoundly effective in cancer cell lines that have been chosen to show signs of resistance to current therapy. Each of the 60 cell lines in the NCI panel has shown dose-dependent cytotoxicity at plasma concentrations that can hinder the growth of tumors in vivo. Arun Rajan and the National Cancer Institute (NCI), United States, have started a clinical trial [registered number-NCT01445106] for the same with the goals of correlating the pharmacokinetics of nelfinavir with the baseline activity of CYP3A4. The studies were performed by measuring midazolam clearance and preliminary examining the biological and clinical impacts using several correlative studies that included blood and tissue analysis across all research subjects.²⁶

With reference to Fig. 4 representing the mechanism of action of the existing antifungal drugs, it is evident that they work by either inhibiting the transcription of RNA / synthesis of DNA at the nucleic acid level. At the cellular level, they inhibit the synthesis of ergosterol thereby damaging the fungal cell membrane. Background research on the antifungal and potent antiviral compounds identified specifically has a significant dual effect on other receptors. Consequently, these medications can be repurposed to treat chronic illnesses as well as more recent viral infections that are spreading globally. This review article goals are to assist the researcher in transitioning forward with cutting-edge discoveries. According to our knowledge, antifungal and antiviral medications can also operate as life-saving treatments, but the discovery still leaves several medications with room for improvement, such as demonstrating their effectiveness in wet laboratory testing. For example, Azoles are a class of antifungal drugs that have a modus operandi of blocking ergosterol synthesis, thereby inhibiting the fungal cell wall synthesis. They can be repurposed as an anticancer agent as they inhibit HDAC as well as cancer cell survival, invasion, angiogenesis, and metastasis. They also reduce the production of cytokines and control the inflammatory pathways of cancer cells. Although a drug is reprofiled for newer indications, quantifying the effective dose, designing of the dosage forms, investigation of its therapeutic effectiveness, and identifying the appropriate route of administration still prove to be a challenge.