Nat Commun. 2023 Feb 22;14(1):993. doi: 10.1038/s41467-023-36637-3.

ABSTRACT

Single-cell RNA sequencing technology has enabled in-depth analysis of intercellular heterogeneity in various diseases. However, its full potential for precision medicine has yet to be reached. Towards this, we propose A Single-cell Guided Pipeline to Aid Repurposing of Drugs (ASGARD) that defines a drug score to recommend drugs by considering all cell clusters to address the intercellular heterogeneity within each patient. ASGARD shows significantly better average accuracy on single-drug therapy compared to two bulk-cell-based drug repurposing methods. We also demonstrated that it performs considerably better than other cell cluster-level predicting methods. In addition, we validate ASGARD using the drug response prediction method TRANSACT with Triple-Negative-Breast-Cancer patient samples. We find that many top-ranked drugs are either approved by the Food and Drug Administration or in clinical trials treating corresponding diseases. In conclusion, ASGARD is a promising drug repurposing recommendation tool guided by single-cell RNA-seq for personalized medicine. ASGARD is free for educational use at https://github.com/lanagarmire/ASGARD .

PMID:36813801 | DOI:10.1038/s41467-023-36637-3

J Infect Public Health. 2023 Feb 10;16(4):554-572. doi: 10.1016/j.jiph.2023.02.005. Online ahead of print.

ABSTRACT

BACKGROUND: The emergence of various drug-resistant strains of Mycobacterium tuberculosis compelled medicinal chemists to expedite the discovery of novel, safer alternatives to present regimens. Decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1), an essential component of arabinogalactan biosynthesis, has been considered a novel target for developing new inhibitors against Tuberculosis. We aimed to discover DprE1 inhibitors utilizing the drug repurposing approach.

METHODS: A structure-based virtual screening of FDA and world-approved drugs database was carried out, and initially, 30 molecules were selected based on their binding affinity. These compounds were further analyzed by molecular docking with extra-precision mode, MMGBSA binding free energy estimation, and prediction of ADMET profile.

RESULTS: Based on the docking results and MMGBSA energy values- ZINC000006716957, ZINC000011677911, and ZINC000022448696 were identified to be the top three hit molecules with good binding interactions inside the active site of DprE1. These hit molecules were subjected to molecular dynamics (MD) simulation for a period of 100 ns to study the dynamic nature of the binding complex. MD results were in accordance with molecular docking and MMGBSA analysis showing protein-ligand contacts with key amino acid residues of DprE1.

CONCLUSION: Based on their stability throughout the 100 ns simulation, ZINC000011677911 was the best in silico hit with an already known safety profile. This molecule could lead to future optimization and development of new DprE1 inhibitors.

PMID:36812878 | DOI:10.1016/j.jiph.2023.02.005

J Mycol Med. 2023 Feb 11;33(2):101361. doi: 10.1016/j.mycmed.2023.101361. Online ahead of print.

ABSTRACT

INTRODUCTION: The treatment of Cryptococcus neoformans with fluconazole and amphotericin B is, at times, characterised by clinical failure. Therefore, this study sought to re-purpose primaquine (PQ) as an anti-Cryptococcus compound.

METHOD: The susceptibility profile of some cryptococcal strains towards PQ was determined using EUCAST guidelines, and PQ's mode of action was examined. In the end, the ability of PQ to enhance in vitro macrophage phagocytosis was also assessed.

RESULTS: We show that PQ had a significant inhibitory effect on the metabolic activity of all tested cryptococcal strains, with 60 µM, defined as MIC50 in this preliminary study, as it reduced the metabolic activity by more than 50%. Moreover, at this concentration, the drug was able to affect mitochondrial function adversely, as treated cells displayed significant (p < 0.05) loss of mitochondrial membrane potential, cytochrome c (cyt c) leakage and overproduction of reactive oxygen species (ROS) when compared to non-treated cells. It is our reasoned summation that the produced ROS targeted the cell walls and cell membranes, inducing observable ultrastructural changes and a significant (p < 0.05) increase in membrane permeability when compared to non-treated cells. Concerning the PQ effect on macrophages, it was noted that it significantly (p < 0.05) enhanced macrophage phagocytic efficiency compared to non-treated macrophages.

CONCLUSION: This preliminary study highlights the potential of PQ to inhibit the in vitro growth of cryptococcal cells. Moreover, PQ could control the proliferation of cryptococcal cells inside macrophages, which they often manipulate in a Trojan horse-like manner.

PMID:36812704 | DOI:10.1016/j.mycmed.2023.101361

Pharmacol Rep. 2023 Feb 21. doi: 10.1007/s43440-023-00461-9. Online ahead of print.

ABSTRACT

BACKGROUND: Peripheral nerve injuries negatively impact the quality of life of patients, with no effective treatment available that accelerates sensorimotor recovery and promotes functional improvement and pain relief. The aim of this study was to evaluate the effects of diacerein (DIA) in an experimental mice model of sciatic nerve crush.

METHOD: In this study, male Swiss mice were used, randomly separated into six groups as follows: FO (false-operated + vehicle); FO + DIA (false-operated + diacerein 30 mg/kg); SNI (sciatic nerve injury + vehicle); SNI + DIA in doses of 3, 10 and 30 mg/kg (sciatic nerve injury + treatment with diacerein in doses of 3-30 mg/kg). DIA or vehicle was administered 24 h after the surgical procedure, intragastrically, twice a day. The lesion of the right sciatic nerve was generated by crush.

RESULTS: We found that the treatment of animals with DIA accelerated sensorimotor recovery of the animal. In addition, animals in the sciatic nerve injury + vehicle (SNI) group showed hopelessness, anhedonia, and lack of well-being, which were significantly inhibited by DIA treatment. The SNI group showed a reduction in the diameters of nerve fibers, axons, and myelin sheaths, while DIA treatment recovered all these parameters. In addition, the treatment of animals with DIA prevented an increase the levels of interleukin (IL)-1β and a reduction in the levels of the brain-derived growth factor (BDNF).

CONCLUSIONS: Treatment with DIA reduces hypersensitivity and depression like behaviors in animals. Furthermore, DIA promotes functional recovery and regulates IL-1β and BDNF concentrations.

PMID:36809646 | DOI:10.1007/s43440-023-00461-9

Rev Environ Health. 2023 Feb 22. doi: 10.1515/reveh-2023-0001. Online ahead of print.

ABSTRACT

The growing concern about the monkeypox (Mpox) virus infection has garnered a lot of public attention. However, the treatment options available to combat the same is limited to tecovirimat. Additionally, in a possible incidence of resistance, hypersensitivity, or adverse drug reaction, it is imperative to devise and reinforce the second-line therapy. Thus, in this editorial, the authors suggest seven antiviral drugs that could potentially be repurposed to combat the viral illness.

PMID:36809250 | DOI:10.1515/reveh-2023-0001

Assay Drug Dev Technol. 2023 Feb 21. doi: 10.1089/adt.2023.008. Online ahead of print.

NO ABSTRACT

PMID:36809110 | DOI:10.1089/adt.2023.008

J Mol Model. 2023 Feb 20;29(3):70. doi: 10.1007/s00894-023-05457-z.

ABSTRACT

BACKGROUND: In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron.

METHODS: As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.

RESULTS: The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of - 75.7304 ± 0.98324 and - 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study.

PMID:36808314 | DOI:10.1007/s00894-023-05457-z

Cell Rep. 2023 Feb 17;42(2):112137. doi: 10.1016/j.celrep.2023.112137. Online ahead of print.

ABSTRACT

Commonly used antihistamines and other cationic amphiphilic drugs (CADs) are emerging as putative cancer drugs. Their unique chemical structure enables CADs to accumulate rapidly inside lysosomes, where they increase lysosomal pH, alter lysosomal lipid metabolism, and eventually cause lysosomal membrane permeabilization. Here, we show that CAD-induced rapid elevation in lysosomal pH is caused by a lysosomal H+ efflux that requires P2RX4-mediated lysosomal Ca2+ release and precedes the lysosomal membrane permeabilization. The subsequent cytosolic acidification triggers the dephosphorylation, lysosomal translocation, and inactivation of the oncogenic signal transducer and activator of transcription 3 (STAT3) transcription factor. Moreover, CAD-induced lysosomal H+ efflux sensitizes cancer cells to apoptosis induced by STAT3 inhibition and acts synergistically with STAT3 inhibition in restricting the tumor growth of A549 non-small cell lung carcinoma xenografts. These findings identify lysosomal H+ efflux and STAT3 inhibition as anticancer mechanisms of CADs and reinforce the repurposing of safe and inexpensive CADs as cancer drugs with a drug combination strategy.

PMID:36807142 | DOI:10.1016/j.celrep.2023.112137

Comput Biol Med. 2023 Feb 12;155:106671. doi: 10.1016/j.compbiomed.2023.106671. Online ahead of print.

ABSTRACT

De novo drug development is an extremely complex, time-consuming and costly task. Urgent needs for therapies of various diseases have greatly accelerated searches for more effective drug development methods. Luckily, drug repurposing provides a new and effective perspective on disease treatment. Rapidly increased large-scale transcriptome data paints a detailed prospect of gene expression during disease onset and thus has received wide attention in the field of computational drug repurposing. However, how to efficiently mine transcriptome data and identify new indications for old drugs remains a critical challenge. This review discussed the irreplaceable role of transcriptome data in computational drug repurposing and summarized some representative databases, tools and strategies. More importantly, it proposed a practical guideline through establishing the correspondence between three gene expression data types and five strategies, which would facilitate researchers to adopt appropriate strategies to deeply mine large-scale transcriptome data and discover more effective therapies.

PMID:36805225 | DOI:10.1016/j.compbiomed.2023.106671

J Invest Dermatol. 2023 Feb 16:S0022-202X(23)00090-8. doi: 10.1016/j.jid.2023.01.024. Online ahead of print.

ABSTRACT

The prevalence of fibrotic diseases and the lack of pharmacologic modalities to effectively treat them impart particular importance to the discovery of novel anti-fibrotic therapies. The repurposing of drugs with existing mechanisms of action and/or clinical data is a promising approach for treatment of fibrotic diseases. One paradigm that pervades all fibrotic disease is the pathological myofibroblast, a collagen-secreting, contractile mesenchymal cell that is responsible for deposition of fibrotic tissue. Here we use a gene expression paradigm characteristic of activated myofibroblasts in combination with the Connectivity Map in order to select compounds that are predicted to reverse the pathological gene expression signature associated with the myofibroblast and, thus, contain potential for use as anti-fibrotic compounds. We tested a small list of these compounds in a first-pass screen, applying them to human fibroblasts, and identified the retinoic acid receptor agonist Ch55 as potential hit. Further investigation exhibited and elucidated anti-fibrotic effects of Ch55 in vitro, as well as demonstrated anti-scarring activity upon intradermal application in a pre-clinical rabbit ear hypertrophic scar model. We hope that similar predictions to uncover anti-scarring compounds may yield further pre-clinical and, ultimately, clinical success.

PMID:36804965 | DOI:10.1016/j.jid.2023.01.024

Bioorg Med Chem. 2023 Feb 11;81:117212. doi: 10.1016/j.bmc.2023.117212. Online ahead of print.

ABSTRACT

Among the various bacterial infections, tuberculosis continues to hold center stage. Its causative agent, Mycobacterium tuberculosis, possesses robust defense mechanisms against most front-line antibiotic drugs and host responses due to their complex cell membranes with unique lipid molecules. It is now well-established that bacteria change their membrane composition to optimize their environment to survive and elude drug action. Thus targeting membrane or membrane components is a promising avenue for exploiting the chemical space focussed on developing novel membrane-centric anti-bacterial small molecules. These approaches are more effective, non-toxic, and can attenuate resistance phenotype. We present the relevance of targeting the mycobacterial membrane as a practical therapeutic approach. The review highlights the direct and indirect targeting of membrane structure and function. Direct membrane targeting agents cause perturbation in the membrane potential and can cause leakage of the cytoplasmic contents. In contrast, indirect membrane targeting agents disrupt the function of membrane-associated proteins involved in cell wall biosynthesis or energy production. We discuss the chronological chemical improvements in various scaffolds targeting specific membrane-associated protein targets, their clinical evaluation, and up-to-date account of their ''mechanisms of action, potency, selectivity'' and limitations. The sources of anti-TB drugs/inhibitors discussed in this work have emerged from target-based identification, cell-based phenotypic screening, drug repurposing, and natural products. We believe this review will inspire the exploration of uncharted chemical space for informing the development of new scaffolds that can inhibit novel mycobacterial membrane targets.

PMID:36804747 | DOI:10.1016/j.bmc.2023.117212

Recent Adv Antiinfect Drug Discov. 2023 Feb 20. doi: 10.2174/2772434418666230220123217. Online ahead of print.

ABSTRACT

BACKGROUND: Since leprosy bacilli cannot grow in vitro, testing for antimicrobial resistance against Mycobacterium leprae or assessing the anti-leprosy activity of new drugs remains hard. Furthermore, developing a new leprosy drug through the traditional drug development process is not economically captivating for pharmaceutical companies. As a result, repurposing existing drugs/approved medications or their derivatives to test their anti-leprotic potency is a promising alternative. It is an accelerated method to uncover different medicinal and therapeutic properties in approved drug molecules.

AIM: The study aims to explore the binding potential of anti-viral drugs such as Tenofovir, Emtricitabine, and Lamivudine (TEL) against Mycobacterium leprae using molecular docking.

METHODS: The current study evaluated and confirmed the possibility of repurposing anti-viral drugs such as TEL (Tenofovir, Emtricitabine, and Lamivudine) by transferring the graphical window of the BIOVIA DS2017 with the Crystal Structure of a phosphoglycerate mutase gpm1 from Mycobacterium leprae (PDB ID:4EO9). Utilizing the smart minimizer algorithm, the protein's energy was reduced in order to achieve a stable local minima conformation.

RESULTS: The protein and molecule energy minimization protocol generated stable configuration energy molecules. The protein 4EO9 energy was reduced from 14264.5 kcal/mol to -17588.1 kcal/mol.

CONCLUSION: The CHARMm algorithm-based CDOCKER run docked all three molecules (TEL) inside the 4EO9 protein binding pocket (Mycobacterium leprae). The interaction analysis revealed that tenofovir had a better binding molecule with a score of -37.7297 kcal/mol than the other molecules.

PMID:36803758 | DOI:10.2174/2772434418666230220123217

J Cardiovasc Pharmacol Ther. 2023 Jan-Dec;28:10742484231156318. doi: 10.1177/10742484231156318.

ABSTRACT

INTRODUCTION: Both exercise and pre-meal metformin could lower postprandial glucose and lipid profiles.

AIMS: To explore whether pre-meal metformin administration is superior to metformin administration with the meal in reducing postprandial lipid and glucose metabolism, and whether its combination with exercise confer superior benefits in metabolic syndrome patients.

MATERIALS AND METHODS: In a randomized crossover design, 15 metabolic syndrome patients were assigned to 6 sequences including 3 experimental conditions: metformin administration with a test meal (met-meal), metformin administration 30 min prior to a test meal (pre-meal-met) with or without an exercise bout designed to expend 700 Kcal at 60% VO2 peak performed the evening just before pre-meal-met condition. Only 13 participants (3 males, 10 females; age: 46 ± 9.86, HbA1c: 6.23 ± 0.36) were included in the final analysis.

RESULTS: Postprandial triglyceridemia was unaffected by any condition (all P > .05). However, both pre-meal-met (-7.1%, P = .009) and pre-meal-metx (-8.2%, P = .013) significantly reduced total cholesterol AUC with no significant differences between the two latter condition (P = .616). Similarly, LDL-cholesterol levels were significantly lower during both pre-meal-met (-10.1%, P = .013) and pre-meal-metx (-10.7%, P = .021) compared to met-meal with no difference between latter conditions (P = .822). Plasma glucose AUC was significantly reduced by pre-meal-metx compared to both pre-meal-met (-7.5%, P = .045) and met-meal (-8%, P = .03). Insulin AUC was significantly lower during pre-meal-metx compared to met-meal (-36.4%, P = .044).

CONCLUSIONS: Metformin administration 30 minutes prior to meal seems to exert favorable effects on postprandial TC and LDL-Cholesterol levels compared to its administration with meal. Addition of one exercise bout only improved postprandial glycemia and insulinemia.

TRIAL REGISTRY: Pan African clinical trial registry, Identifier PACTR202203690920424.

PMID:36802839 | DOI:10.1177/10742484231156318

Int J Pharm. 2023 Feb 18:122759. doi: 10.1016/j.ijpharm.2023.122759. Online ahead of print.

ABSTRACT

The blood-brain barrier (BBB) limits the access of substances to the central nervous system (CNS) which hinders the treatment of pathologies affecting the brain and the spinal cord. Nowadays, research is focus on new strategies to overcome the BBB and can treat the pathologies affecting the CNS are needed. In this review, the different strategies that allow and increase the access of substances to the CNS are analysed and extended commented, not only invasive strategies but also non-invasive ones. The invasive techniques include the direct injection into the brain parenchyma or the CSF and the therapeutic opening of the BBB, while the non-invasive techniques include the use of alternative routes of administration (nose-to-brain route), the inhibition of efflux transporters (as it is important to prevent the drug efflux from the brain and enhance the therapeutic efficiency), the chemical modification of the molecules (prodrugs and chemical drug delivery systems (CDDS)) and the use of nanocarriers. In the future, knowledge about nanocarriers to treat CNS diseases will continue to increase, but the use of other strategies such as drug repurposing or drug reprofiling, which are cheaper and less time consuming, may limit its transfer to society. The main conclusion is that the combination of different strategies may be the most interesting approach to increase the access of substances to the CNS.

PMID:36801479 | DOI:10.1016/j.ijpharm.2023.122759

Stem Cell Reports. 2023 Feb 15:S2213-6711(23)00011-5. doi: 10.1016/j.stemcr.2023.01.008. Online ahead of print.

ABSTRACT

Improving methods for human embryonic stem cell differentiation represents a challenge in modern regenerative medicine research. Using drug repurposing approaches, we discover small molecules that regulate the formation of definitive endoderm. Among them are inhibitors of known processes involved in endoderm differentiation (mTOR, PI3K, and JNK pathways) and a new compound, with an unknown mechanism of action, capable of inducing endoderm formation in the absence of growth factors in the media. Optimization of the classical protocol by inclusion of this compound achieves the same differentiation efficiency with a 90% cost reduction. The presented in silico procedure for candidate molecule selection has broad potential for improving stem cell differentiation protocols.

PMID:36801003 | DOI:10.1016/j.stemcr.2023.01.008

Int J Surg. 2023 Jan 1;109(1):60-61. doi: 10.1097/JS9.0000000000000010.

NO ABSTRACT

PMID:36799796 | DOI:10.1097/JS9.0000000000000010

OMICS. 2023 Feb 17. doi: 10.1089/omi.2022.0185. Online ahead of print.

ABSTRACT

Cancer and arachidonic acid (AA) have important linkages. For example, AA metabolites regulate several critical biological functions associated with carcinogenesis: angiogenesis, apoptosis, and cancer invasion. However, little is known about the comparative changes in metabolite expression of the arachidonic acid pathway (AAP) in carcinogenesis. In this study, we examined transcriptome data from 12 cancers, such as breast invasive carcinoma, colon adenocarcinoma, lung adenocarcinoma, and prostate adenocarcinoma. We also report here a reverse-engineering strategy wherein we estimated metabolic signatures associated with AAP by (1) making deductive inferences through transcriptome-level data extraction, (2) remodeling AA metabolism, and (3) performing a comparative analysis of cancer types to determine the similarities and differences between different cancer types with respect to AA metabolic alterations. We identified 77 AAP gene signatures differentially expressed in cancers and 37 AAP metabolites associated with them. Importantly, the metabolite 15(S)-HETE was identified in almost all cancers, while arachidonate, 5-HETE, PGF2α, 14,15-EET, 8,9-EET, 5,6-EET, and 20-HETE were discovered as other most regulated metabolites. This study shows that the 12 cancers studied herein, although in different branches of the AAP, have altered expression of AAP gene signatures. Going forward, AA related-cancer research generally, and the molecular signatures and their estimated metabolites reported herein specifically, hold broad promise for precision/personalized medicine in oncology as potential therapeutic and diagnostic targets.

PMID:36800175 | DOI:10.1089/omi.2022.0185

J Comp Eff Res. 2023 Feb 17:e220136. doi: 10.57264/cer-2022-0136. Online ahead of print.

ABSTRACT

Aim: To evaluate the performance of the multiple imputation (MI) method for estimating clinical effectiveness in pediatric Crohn's disease in the ImproveCareNow registry; to address the analytical challenge of missing data. Materials & methods: Simulation studies were performed by creating missing datasets based on fully observed data from patients with moderate-to-severe Crohn's disease treated with non-ustekinumab biologics. MI was used to impute sPCDAI remission statuses in each simulated dataset. Results: The true remission rate (75.1% [95% CI: 72.6%, 77.5%]) was underestimated without imputation (72.6% [71.8%, 73.3%]). With MI, the estimate was 74.8% (74.4%, 75.2%). Conclusion: MI reduced nonresponse bias and improved the validity, reliability, and efficiency of real-world registry data to estimate remission rate in pediatric patients with Crohn's disease.

PMID:36799351 | DOI:10.57264/cer-2022-0136

ACS Pharmacol Transl Sci. 2023 Jan 12;6(2):281-289. doi: 10.1021/acsptsci.2c00214. eCollection 2023 Feb 10.

ABSTRACT

Cancer treatment by inhibiting the PD-1/PD-L1 pathway using monoclonal antibodies has made great advances as it showed long-lasting antitumor responses in a wide range of cancers. However, antibodies exhibit several disadvantages, which include low permeability, immune-related adverse effects, complex synthetic procedures, and high treatment costs. Hence, small-molecule inhibitors can be used as alternatives; however, no small molecule with in vivo activity has been reported. In addition, there are many challenges in developing a new drug, including the timeline and escalating cost. Therefore, repurposing an approved drug offers advantages over the development of an entirely new drug. Herein, we identify an FDA-approved small-molecule drug, Ponatinib, as a PD-L1 inhibitor via virtual drug screening of the ZINC database. Ponatinib showed stable binding with PD-L1, with the highest binding energy among all of the screened FDA-approved drugs. The binding of Ponatinib with PD-L1 was supported by a fluorescence quenching assay and immunofluorescence study. Further, we compared the in vivo antitumor efficacy of Ponatinib with a commercially available anti-PD-L1 antibody in the murine melanoma model. Ponatinib was found to be more efficient in delaying tumor growth than the anti-PD-L1 antibody. Furthermore, Ponatinib also reduced the expression of PD-L1 in tumors and increased the T-cell population. Interestingly, splenocytes isolated from Ponatinib-treated mice showed enhanced cytotoxic T-cell (CTL) activity against B16-F10 cells. However, Ponatinib itself did not have any direct toxic effect on cancer cells in vitro. These findings suggest that Ponatinib can be used as a potent small-molecule inhibitor of PD-L1 to overcome the disadvantages associated with antibodies.

PMID:36798474 | PMC:PMC9926522 | DOI:10.1021/acsptsci.2c00214

ACS Pharmacol Transl Sci. 2023 Jan 17;6(2):201-219. doi: 10.1021/acsptsci.2c00151. eCollection 2023 Feb 10.

ABSTRACT

Drug repurposing toward new medical uses and chiral switches are elements of secondary pharmaceuticals. The drug repurposing and chiral-switches strategies have mostly been applied independently in drug discovery. Drug repurposing has peaked in the search for therapeutic treatments of the Coronavirus Disease 2019 pandemic, whereas chiral switches have been overlooked. The current Perspective introduces the drug repurposing/chiral-switches combination strategy, overviewing representative cases of chiral drugs that have undergone this combination: ketamine, flurbiprofen, fenfluramine, and milnacipran. The deuterium-enabled chiral switches of racemic thalidomide analogs, a variation of the repurposing/chiral-switch combination strategy, is also included. Patenting and regulatory-exclusivity considerations of the combination strategy in the discovery of new medical uses are considered. The proposed combination creates a new synergy of its two elements, overcoming arguments against chiral switches, with better prospects for validation of patents and regulatory exclusivities. The combination strategy may be applied to chiral switches to paired enantiomers. Repurposing/chiral-switch drugs may be 'obvious-to-try'; however, their inventions may be unexpected and their patents nonobvious. Patenting repurposing/chiral-switch combination drugs is not 'evergreening', 'product hopping', and 'me-too'. The expected benefits and opportunities of the combined repurposing/chiral-switch strategy vis-à-vis its two elements are superior pharmacological properties, overcoming arguments against patent validities, challenges of chiral-switch patents, reduced expenses, shortened approval procedures, and higher expectations of regulatory exclusivities.

PMID:36798472 | PMC:PMC9926527 | DOI:10.1021/acsptsci.2c00151