key: cord-1015924-zbt4bo4f
authors: Schein, Catherine H.
title: Repurposing approved drugs on the pathway to novel therapies
date: 2019-08-20
journal: Med Res Rev
DOI: 10.1002/med.21627
sha: 5e127d4a0c23e59e8f9c24aa988a81547e83f225
doc_id: 1015924
cord_uid: zbt4bo4f

The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

Section 3 is devoted to the difficulties in repurposing drugs and natural products, and how older drugs may be repurposed to overcome these. Many approved drugs have low solubility, lack specificity, and may require unrealistic dosing for uses beyond their initial target (Section 3.1). Dosages that may be well tolerated in trials conducted using healthy subjects (or in the case of animal studies, healthy until infected) may not be achievable in the clinic. Patients in the clinic or field hospital are very sick when they present and have comorbidities. Burn, cancer, Ebola, and other emerging infection victims are fragile patients. They will thus be more likely to suffer side effects at high doses. Collaboration with medicinal chemists at an early stage in development can insure more specific and potent therapies for testing. In Section 3. The many current uses of thalidomide represent perhaps the most spectacular example of how an old drug can assume new roles. 22 Thalidomide (Table 1) was originally introduced by Grünenthal Chemie in the mid-1950s, and by 1957 was available over the counter in several European countries for treating insomnia and morning sickness.

The drug was not approved by the US-FDA, as the young examiner assigned to the thalidomide application noted defects in its safety profile. She was especially concerned about severe peripheral neuritis reported as a possible side effect. 23 Thus, even without teratogenicity testing, thalidomide's potential to cause dangerous side effects was clear before 1960. Thalidomide was withdrawn worldwide in 1962 only after it became notorious for causing severe birth defects. The drug's other associated side effects, including rash, tremor, hypothyroidism, hypocalcemia, hyperkalemia, and toxic epidermal necrolysis (in 3%-4% of patients) would seem to have doomed it to a mere cautionary tale in the history of pharmacy.

Yet thalidomide soon rose from the ashes. By the mid-1960s, it was being used to treat skin lesions and granulomas associated with leprosy. Today, thalidomide is part of the first-line treatment for Hanson's disease.

Curiously, its ability to bind to cereblon, 24 a protein involved in limb outgrowth, which is believed to be at the root of its teratogenic effects, may also enable it to control the growth of multiple myeloma cells. 25 More potent derivatives, such as lenalidomide and pomalidomide (Table 1) have been approved by the FDA to treat multiple myeloma, 25 mantle cell lymphoma, and myelodysplastic syndromes associated with the deletion 5q abnormality.

Thalidomide and its derivatives inhibit secretion of tumor necrosis factor (TNF)-α and other inflammatory cytokines, 26 by direct and indirect effects on cells. 27 This has led to many tests for their abilities to ease inflammation.

Low dose thalidomide (50-150 mg/day) alleviated the symptoms of patients with Crohn's disease who were refractory to many other treatments. 28 Thalidomide also alleviates the cytokine storm induced by bacterial infections. 29 Animal studies indicate thio-derivatives, such as 3.6'-dithiothalidomide, might be useful for the treatment of aneurysms 30 and traumatic brain injury. 31 The more specific PDE4 inhibitor, apremilast, 32, 33 can alleviate several diseases associated with overexpression of TNF-α, such as psoriasis, lupus erythematosus, and rheumatoid arthritis. 34 Lenalidomide treatment may even restore color to gray hair 35 ! While this might be related to other effects of TNF-ɑ on regulating hair growth, 36, 37 it should be noted that other therapies, such as tyrosine kinase inhibitors, 38 may also affect hair color. "Repigmentation", in this case, darkening of hair, has also been seen during therapy with PD-L1 inhibitors. The authors describe repigmentation as a side effect and possible clinical marker for successful treatment. 39 

Recent government support has led to many more approved drugs being tested for applications far beyond their initial use. For example, drugs that have "antitussive, sedative, analgesic, antipyretic, antiarthritic, anesthetic, antidiabetic, muscle relaxant, immunosuppressant, antibiotic, antiepileptic, cardioprotective, antihypertensive, erectile function enhancing, or angina relieving" properties may be used as adjuvant therapies in cancer. 13 A few examples of repurposed drugs that are being tested in select groups of patients or have entered clinical trials are shown in Table 2 .

The effort to reuse existing drugs for novel therapies is especially important for rare diseases, where the patient population is too small to justify the major effort needed to introduce a new drug. Alternatively, it may be the only way to identify treatments for severe diseases with idiopathic etiology, such as neurofibromatosis. 58 As Table 2 indicates, repurposing may provide alternative treatments for psychiatric disorders. The antioxidant ebselen has been tested to treat bipolar disorder in patients who cannot tolerate lithium treatment, while loxapine may treat irritability associated with autism. Antiinflammatory drugs, as well as a variety of other repurposed compounds, have also been suggested as alternative treatments for schizophrenic patients. These include acetylsalicylic acid, celecoxib, minocycline, N-acetylcysteine, and nutraceuticals. 59 clinically important microbes are survivors of these battles, meaning they typically possess powerful defensive weapons consisting of an array of toxins, enzymes to degrade or export antibiotics, and other tools to deal with serum proteases and the mammalian immune system. In the face of antibiotic treatment, the enzymes in this arsenal evolve to meet the new challenge.

In the past, older antibiotics were constantly being superseded by newer ones, designed to evade the latest resistance mechanism found in clinical isolates. However, many companies have dropped programs to develop new antiinfectives, due to the time and cost of clinical trials. The lack of new drugs has given a strong incentive to repurpose older antibiotics for multidrug-resistant strains or to combine them with agents that can target several different pathways in the pathogen, or activate host cell resistance pathways. This should lead to enhanced activity and lower the chances for development of resistance. 60 Reverting to older antibiotics can, in some cases, overcome antibiotic resistance. For example, TB strains resistant to currently used drug combinations are found in all parts of the world. One of the most useful TB drugs, isoniazid, inhibits the enzyme InhA, blocking the synthesis of the mycolic acids that make up the cell wall of the mycobacterium. Much of the resistance to isoniazid, a prodrug, comes from mutations in the bacterial enzymes required to activate it. It has recently been found that an older natural product antibiotic, pyridomycin, discovered in the 1950s, inhibits InhA directly. Thus it can be used to treat infections with resistant TB strains that survive by their lack of ability to activate isoniazid. 61 Understanding this mechanism of action may also advance the use of pyridomycin in conjunction with other drugs. 62

The era of antibiotic resistance has also brought a new interest in combining older antibiotics with compounds that can enhance their activity. 63 Many compounds have been developed to specifically block bacterial enzymes that mediate resistance. 64 Combining penicillin derivatives with β-lactamase inhibitors can overcome bacterial resistance in many cases. 19 For example, one can pair piperacillin with tazobactam, a competitive inhibitor of βlactamases that protects the paired antibiotic from degradation. The mechanisms of β-lactamases and their respective inhibitors that have been successfully combined with antibiotics are discussed in several comprehensive reviews. 65, 66 While combination therapy has advantages, the rapid rise of resistance mutations in bacteria 67 can complicate the choice of combinations to yield the best synergy among treatments. 68 Determining the most effective adjuvants to complement antibiotics to better treat resistant bacteria should be aided by a new "antibiotic resistance platform" (ARP). The ARP is an array of transformed Escherichia coli that expresses one of greater than 40 different known antibiotic resistance genes. This allows screening for compounds that either target the resistance gene or otherwise potentiate the antibacterial activity of a given antibiotic. 69 Other efforts are being made to design combination therapies for fungal infections. 70 

Combining antibiotics with agents that inhibit toxins or other effectors that contribute to their pathogenicity can also enhance their activity. Tissue damage and immune activation are caused by bacterially produced toxins, including proteases, pyrolytic toxins, "superantigens" 71 and those that elevate tissue cyclic adenosine monophosphate levels. 72 Antibiotics can have additional activities that may lead to synergy or antagonism of toxin production. For example, β-lactam antibiotics can increase the production of bacterial toxins in Staphylococcus aureus , while those that inhibit protein synthesis, such as clindamycin, greatly reduce them. 73 As toxins mediate pathogenic effects even after the death of the bacteria, direct inhibitors of bacterial toxins may aid in controlling symptoms when used alone or in combination with antibiotics. 15, [74] [75] [76] Further, as discussed in the next sections, patients may benefit from alternative application modes and cotreatment with antibiotics and other compounds designed to directly target pathways in human cells.

The application mode of antibiotics can also affect their activity. While oral availability is prized, inpatients are frequently treated with antibiotic infusions or direct injection.

Inhaling a drug may give completely different activities than injection or infusion. Recent experiments in pigs with deleted cystic fibrosis transmembrane receptor (CFTR) have shown that an aerosol treatment with amphotericin B, a toxic antifungal agent, formulated in liposomes with cholesterol, restored airway pH levels. The authors suggest that similar aerosol treatment would help CF patients with many different CFTR mutations. 77 Similarly, inhalation may also improve the ability of type-1 interferon to treat Epstein-Barr virus. 78 interferon (IFN)-ɣ, which has mechanisms of action that differ from type-1 interferons, 79 such as in its ability to directly control ribonucleases, 80, 81 was originally used as an antiviral and immune activator. Currently, it is used via subcutaneous injection to treat chronic granulomatous disease and osteopetrosis. In a controlled clinical trial, inhaled IFN-ɣ could control TB, while parenteral IFN-ɣ did not. These results indicate that macrophages can be effectively immune-stimulated by aerosol therapy. Treatment with aerosol IFN-ɣ was well tolerated in a 2-year safety study in patients with idiopathic pulmonary fibrosis, where the decline in pulmonary function was reversed.

The same approach may also be useful for COPD. 82 Other types of drugs may also benefit from changing the mode of application. A drug that shows long term toxicity can still prove valuable when used for short periods of time. For example, mibefradil, originally used for blood pressure control, was withdrawn as chronic use slowed the excretion of as many as 26 other drugs, causing them to accumulate to dangerous levels in the liver. More recently, it was shown that short term dosing with mibefradil can enhance the activity of several different cancer drugs. 52 

Given the rising number of strains found to be resistant to drugs that affect pathways specific to infectious agents, many repurposing studies are now looking for more broad-spectrum agents that block or activate host pathways, such as those targeted in cancer therapy. 13 Drugs developed to inhibit intracellular kinases, 83 whereby full protection required coadministration of vancomycin. 86 The same group found that, at 33 µM, 9% to 13% of 780 tested drugs inhibited the growth of Klebsiella pneumoniae or Acinetobacter baumannii in macrophages.

As noted above, the ability of thalidomide and its derivatives to block TNF-α, a major regulator of the inflammatory response, has led to their use in diseases such as psoriasis and other autoimmune disorders characterized by cytokine overproduction. The tetracycline derivative, doxycycline, can aid in wound healing through inhibiting host metalloproteases that may be causing further tissue injury. 87, 88 Doxycycline can also play a similar role in controlling sepsis. 89 Antiinflammatory compounds, including nonsteroidal antiinflammatory drugs (NSAIDs), can control fever and other aspects of the "cytokine storm" that several different viruses induce. Ibuprofen has been suggested to control Ebola symptoms. 90 NSAIDs can also improve survival in cancers, for example in patients with activating mutations in PIK3CA, which are very common in head and neck cancers. The predicted 5-year disease-specific and overall survival was significantly higher (72% vs 25%; 78% vs 45%, respectively) for those who used NSAIDs regularly than 107 These include those that bind IFN itself, such as rontalizumab 108, 109 and inhibitors of interferon pathway proteins. [110] [111] [112] Autophagy pathways can be specifically targeted, [113] [114] [115] [116] according to the type of virus infection. Inhibitors of autophagy may inhibit the growth of RNA viruses that rely on the associated membranes for replication, such as Picornaviruses 117 and Dengue. 118 However, such inhibitors might favor the lytic growth of herpes and other viruses whose replication is held in check by autophagy. 119, 120 Results of screening drug libraries have revealed several other mammalian cell pathways that may be targeted.

For example, blockers of Ca 2+ and other ion channels are reported to have in vitro activity against Ebola, 17, 121 Japanese Encephalitis virus, 122 human cytomegalovirus 123 and arenaviruses such as Lassa fever. 124 

Simply having the desired activity does not mean that an older drug can move rapidly into the clinic. Older drugs may have significant problems that will interfere with their implementation in modern therapy programs, such as poor physicochemical properties (section 3.1a), significant side effects (3.1b) or requiring unrealistic dosing for use in patients who are already severely ill (3.1c). While repurposing an approved drug may seem to be the most rapid path to treatment, 125 moving too rapidly into clinical testing can interfere with efforts to find more specific treatments. Extreme caution must be taken in identifying the best treatment for rare diseases,

where the patient pool is small and fragile. Creutzfeldt-Jakob disease, as one example, is an extremely rare and rapidly moving syndrome. Many tests of repurposed compounds, including doxycycline, quinacrine, pentosan sulfate, and flupirtine, all failed to have any significant effect on patient survival, due to their lack of specificity. 126 Thus, to enhance specificity and deal with the issues discussed in Section 3.1, as well as licensing considerations, 127 it may be best to regard that first active, approved drug as a starting point for developing a therapeutic. Collaboration with a medicinal chemistry group or company can promote access to derivatives with better specific activities, more suitable physicochemical properties, or reduced side effects (Section 3.2).

3.1 | Obstacles to overcome in repurposing

For example, fluorescein derivatives of rose bengal dye, approved for food use and a common laboratory stain, were first used medicinally to treat ocular infections in 1914. Thanks to its low toxicity, rose bengal therapies quickly entered the clinic. Today, topical versions of the dye are being tested for reducing scarring after injury or burns. 128 The molecule became even more interesting when testing in the 1980s indicated it inhibited the growth of tumor cells. A formulation, PV-10, is in clinical trials for treating tumors. 129 However, large amounts of the dye are required as the compound has only a 30-minute half-life in serum and as Figure 1 illustrates, it is a large hydrophobic molecule with limited solubility. The results of these trials may be used to obtain derivatives with better pharmaceutical characteristics, designed for solubility or more specific anticancer activities.

Other FDA-approved drugs are not ideal candidates for further development. 130 Many chemotherapy drugs that require infusion, such as the bright blue compound mitroxantrone, an agent which has a variety of activities in cells, 131 have limited solubility and may induce nonspecific aggregation of the protein or assay reagents in high throughput screening. 132 A good deal of time can be lost to these nonspecific aggregators, which can have misleading activity in a variety of different assays at low micromolar concentrations. 6 Mitroxantrone even turned up in a preliminary screen to identify inhibitors of uridylyation of the peptide linked to the genome, VPg, 133 to VPgpU 134 by the coxsackie virus A24 polymerase 135, 136 in the author's group. Several different assays were required to show it precipitated the RNA substrate, rather than specifically inhibiting the polymerase. As with the uridylylation reaction, adding detergents to control aggregation induced by such agents may not be suitable for most assays. The physicochemical properties for drugs, such as solubility, can be obtained from free online databases, including ZINC 137 or OCHEM (http://ochem.eu). 138 

Many FDA-approved drugs, including those used for chemotherapy, have severe side effects that may prevent their use for other purposes. For example, emetine, better known as an active ingredient of ipecac syrup, binds ribosomes 139 and inhibits a variety of disease-causing protozoa. [140] [141] [142] [143] It has also been reported to selectively kill acute myeloid leukemia cells. 144 Emetine was selected by an Ebola minigenome HTS assay (which can be run at BSL-2 level) from a 2080 active component library 145 However, emetine causes severe nausea when taken orally or injected. It remains to be seen whether emetine's side effects can be overcome sufficiently to bring it into the clinic for these indications.

Similarly, the success of the many ongoing trials of calcineurin inhibitors (eg, tacrolimus) for controlling inflammatory bowel disease, atopic dermatitis, rheumatoid arthritis, and autoimmune diseases may be limited by the increased risk of severe infection intrinsic to inhibiting a pathway that is essential for control of bacterial and fungal pathogens. 146 Side effects may also limit the clinical usefulness of a variety of off-the (drug-)-shelf compounds suggested as treatments for serious virus infections. The FDA-approved cancer drug, gemcitabine, inhibits picornaviruses 147 , and other viruses. 148 The bioflavonoid rutin inhibits norovirus. 149 Quinine and other antimalarials have been suggested for flaviviruses such as Dengue 150, 151 and Zika 152 as well as the coronaviruses MERS/SARS. 153 The clinical future of these treatments will depend on whether the side effects during short term administration are acceptable. It may be also possible to identify other known drugs with reduced side effects. A recent paper suggests that by categorizing drugs according to their indications and known side effects, one could identify drugs that could replace those with a "boxed warning" by safer ones with similar efficacy. 154

Another obstacle to repurposing is that higher concentrations of the drug may be needed when used for purposes beyond the original design. High throughput screening for approved drugs may be conducted at concentrations of 33 to 100 µM, where compound screenings of larger compound libraries are done at 10 to 20 µM, followed by dilutions to lower concentrations in secondary assays of initial hits. At high concentrations, drugs may have different mechanisms than those associated with their suggested use in humans. Compounds may bind to off-target molecules that have little to do with the initially determined mechanism of actions, causing side effects when translated to human therapies. Even molecules suggested to be specific, for example, those with high affinity for a G-protein coupled receptor, have been found to bind completely unrelated molecules, such as phosphodiesterases, whereby the binding sites can be very different. 155 Screening a large compound library by docking found many molecules selected to bind to a specific site in fact bound preferentially to a different one when given a larger region of the protein surface to choose from. 136 The inexpensive, orally available nucleotide analogs, ribavirin, and favipiravir (developed for influenza 156 ) , when used at high concentrations, inhibit many viral RNA polymerases by different mechanisms. [157] [158] [159] [160] Favipiravir inhibits Congo hemorrhagic fever virus (CCHF) 161 and Ebola 162 in mice and Ebola 163 and Lassa fever 164 in primate models. It has been used with ribavirin to treat Lassa fever patients. 165 However, favipiravir, even at doses of 150 to 300 mg/kg, did not completely eliminate CCHF in surviving infected mice, with several dying after treatment stopped. About 50% of the Ebola-infected macaques survived, at the highest dose used (180 mg/kg). Although favipiravir is a small and soluble compound (Figure 2) , this is still a very high dose.

When used in combination with oseltamivir (20 mg/kg) to treat influenza, effective doses were in the range of 50 mg/ kg. 166 Attempts to treat Ebola patients during the 2014 epidemic with high doses of favipiravir (1.2-2.4 g/day) 162 gave unacceptable, significant side effects in patients who were more severely ill at presentation. 167 Other nucleotide derivatives may have better potency in treating this disease, 168 which is causing yet another large outbreak.

F I G U R E 2 Favipiravir (T-705, avigan), a pyrazine carboxamide derivative, inhibits many different viral polymerases at high concentrations

In another example of a repurposed drug active only at high concentrations, the antimalarial drug pyrimethamine was found to stabilize β-hexosaminidase, the enzyme defective in Tay-Sachs disease. 169 However, it produced significant side effects at the 75 to 100 mg doses required for efficacy in phases 1 and 2 testings in eight humans with late-onset Tay-Sachs. 170 It was further tested more recently 171 and gave a temporary improvement in measured enzyme activity, with one of four patients remaining stable while the other three continued to deteriorate. Seven years after the initial drug screening, more active forms of pyrimethamine were being sought, 172 with the hope of finding a treatment for this deadly disease.

Despite its worldwide withdrawal from the market in 1962, thalidomide was approved to treat granulomas associated with leprosy in the mid-1960s. This is an example of how, even with obvious side effects, a drug may be used clinically for a specific purpose. While thalidomide treatment will always be limited by its side effects, small changes resulted in much more active molecules that could be used at lower doses (Table 1) . 32, 33 Of course, any derivative must go through toxicity screening and new clinical trials before it can be marketed, which can take considerable time. Thalidomide's active derivatives were approved for specific treatments in 2005 (lenalidomide) and 2013 (pomalidomide).

Similarly, small structural changes may completely alter the spectrum of activity of an antibiotic. Conjugation of daptomycin, an antibiotic targeting Gram-positive bacteria, with an iron-binding siderophore mimetic generated a new series of antibiotics that could penetrate the cell wall of Gram-negative, antibiotic-resistant strains of

Recently approved derivatives of tetracycline (Table 3) also illustrate how small structural changes may enhance a drug's specific activity or ability to evade resistance mechanisms. Tetracyclines block elongation of proteins in bacteria by binding to the 30S ribosomal subunit. New derivatives, such as Nuzyra (omadacycline), an aminomethylcycline, have been designed to overcome bacterial resistance to tetracycline, caused by bacterial efflux pumps (tetK, tetL, tet) or ribosomal protection proteins such as tetM. Nuzyra can be used to treat bacterial pneumonia caused by a variety of resistant bacteria, including S. aureus, and streptococcal strains. 174 Xerava (eravacycline), a synthetic fluorocycline, was developed to treat intra-abdominal infections caused by many different enteric bacteria. 175, 176 In contrast, Seysara (sarecycline), recommended for moderate-to-severe acne vulgaris, has less activity against enteric bacteria but reduces inflammation. 177, 178 Although treatment with these derivatives may save costs, compared with vancomycin, 179 they are still much more expensive than their parent, tetracycline.

Repurposing of older molecules can be a path to finding novel therapies. Screening approved drug libraries may be the most efficient way to identify treatments for rare and emerging diseases. Perhaps the best example of a repurposed drug is thalidomide, which despite its notorious side effects provides a valuable treatment for cancers and granulomas associated with leprosy. Table 2 illustrates how many other drugs are in testing for their usefulness in treating conditions beyond their original targets. Older antibiotics may also be repurposed by combining them with other active compounds, to achieve broad-spectrum activities against infectious agents.

However, many existing drugs have poor physicochemical properties and significant side effects when used at high concentrations. Identifying appropriate derivatives of an approved compound can, in the end, be the fastest path to the clinic. Derivatives of thalidomide and tetracycline provide excellent examples of how relatively small changes in a drug structure can greatly lower the dosage required and alter the spectrum of activity.

While by no means comprehensive, the many examples are shown here illustrate the great promise of the existing pharmacopeia and modifications thereof to treat "the many ills that flesh is heir to".

The author thanks Dr Wendy Baker for her careful reading of this manuscript, the many individuals who sent papers for this review and apologizes in advance for any oversight of pertinent literature. Parts of this work were supported by NIAID R21 AI105985-01 (to CHS) and R01 AI137332-01.

Catherine H. Schein http://orcid.org/0000-0002-8290-2109

Inhibition of adenovirus infection by mifepristone

Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection

Repurposing drugs for use against Zika virus infection

Novel approaches to flavivirus drug discovery

Identification of a compound that disrupts binding of amyloid-β to the prion protein using a novel fluorescence-based assay

Pilot-scale compound screening against RNA editing identifies trypanocidal agents

Studying a drug-like, RNA-focused small molecule library identifies compounds that inhibit RNA toxicity in myotonic dystrophy

The drug repurposing hub: a next-generation drug library and information resource

Systematic analyses of drugs and disease indications in RepurposeDB reveal pharmacological, biological and epidemiological factors influencing drug repositioning

RE:fine drugs': an interactive dashboard to access drug repurposing opportunities

A standard database for drug repositioning

Drug repurposing identifies inhibitors of oseltamivir-resistant influenza viruses

Cancer drug discovery by repurposing: teaching new tricks to old dogs

Impact of delayed appropriate antibiotic therapy on patient outcomes by antibiotic resistance status from serious gram-negative bacterial infections

Novel inhibitors of anthrax edema factor

Pharmacophore selection and redesign of nonnucleotide inhibitors of anthrax edema factor

A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity

Repurposing kinase inhibitors as antiviral agents to control influenza A virus replication

Exploring the potential of adjunct therapy in tuberculosis

Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment

Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space

The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development

Thalidomide update: regulatory aspects

Structural basis of thalidomide enantiomer binding to cereblon

Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma

Lessons of leprosy: the emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity

Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase

Mucosal healing with thalidomide in refractory Crohn's disease patients intolerant of anti-TNF-α drugs: report of 3 cases and literature review

Immune reconstitution inflammatory syndrome associated with bacterial infections

Critical role of TNF-α in cerebral aneurysm formation and progression to rupture

Postinjury neuroprotective effects of the thalidomide analog 3,6′-dithiothalidomide on traumatic brain injury

Immunomodulation by thalidomide and thalidomide analogues

Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha

Apremilast for discoid lupus erythematosus: results of a phase 2, open-label, single-arm, pilot study

Hair repigmentation associated with the use of lenalidomide: graying may not be an irreversible process

Hair regrowth following TNF-α blockade in coexisting psoriasis vulgaris and alopecia areata

Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar

Tyrosine kinase inhibition and grey hair. The Lancet

Hair repigmentation during immunotherapy treatment with an antiprogrammed cell death 1 and antiprogrammed cell death ligand 1 agent for lung cancer

Atorvastatin treatment of cavernous angiomas with symptomatic hemorrhage exploratory proof of concept (AT CASH EPOC) trial. Neurosurgery

The poor design of clinical trials of statins in oncology may explain their failure-lessons for drug repurposing

Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer's and other neurodegenerative diseases? Protocol for an observational cohort study in the UK Clinical Practice Research Datalink

Fenofibrate and telmisartan in the management of abdominal aortic aneurysm

Multiple sclerosis-secondary progressive multiarm randomisation trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes

Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer's disease hallmarks

Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial

Metformin to augment strength training effective response in seniors (MASTERS): study protocol for a randomized controlled trial

γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct

A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease. Alzheimer's Research & Therapy

Repurposing and Rescuing of Mibefradil, an antihypertensive, for cancer: a case study

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

ATTIRE: albumin To prevenT infection in chronic liveR failurE: study protocol for an interventional randomised controlled trial

Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla

Loxapine add-on for adolescents and adults with autism spectrum disorders and irritability

Nitazoxanide: a first-in-class broad-spectrum antiviral agent

Neurofibromatosis as a gateway to better treatment for a variety of malignancies

Drug repurposing and emerging adjunctive treatments for schizophrenia

Drug combinations: a strategy to extend the life of antibiotics in the 21st century

Towards a new tuberculosis drug: pyridomycin-nature's isoniazid

Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline

Inhibitors of metallo-β-lactamases

Antibiotic adjuvants: rescuing antibiotics from resistance

The continuing challenge of metallo-β-lactamase inhibition: mechanism matters

Exploring additional dimensions of complexity in inhibitor design for serine βlactamases: mechanistic and intra-and inter-molecular chemistry approaches

Deciphering the evolution of cephalosporin resistance to ceftolozanetazobactam in pseudomonas aeruginosa. mBio

In vitro comparison of ceftolozane-tazobactam to traditional beta-lactams and ceftolozane-tazobactam as an alternative to combination antimicrobial therapy for pseudomonas aeruginosa

A common platform for antibiotic dereplication and adjuvant discovery

Combinatorial strategies for combating invasive fungal infections

Nasopharyngeal infection by Streptococcus pyogenes requires superantigen-responsive Vβ-specific T cells

Testing the efficacy and toxicity of adenylyl cyclase inhibitors against enteric pathogens using in vitro and in vivo models of infection

Adjunctive protein synthesis inhibitor antibiotics for toxin suppression in Staphylococcus aureus infections: a systematic appraisal

Treatment of clostridium difficile infection with a small-molecule inhibitor of toxin UDP-glucose hydrolysis activity

Structure-based redesign of an edema toxin inhibitor

Functional classification of protein toxins as a basis for bioinformatic screening

Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia

Interferon alpha as antiviral therapy in chronic active Epstein-Barr virus disease with interstitial pneumonia-case report

Direct antiviral mechanisms of interferon-gamma

Deletions at the C-terminus of interferonγreduce RNA binding and activation of doublestranded-RNA cleavage by bovine seminal ribonuclease

From housekeeper to microsurgeon: the diagnostic and therapeutic potential of ribonucleases

Repurposing of gamma interferon via inhalation delivery

Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus fusion

Characterizing protein kinase substrate specificity using the proteomic peptide library (ProPeL) approach

Membrane interaction and functional plasticity of inositol polyphosphate 5-phosphatases

Combating multidrug-resistant pathogens with host-directed nonantibiotic therapeutics

The role of doxycycline as a matrix metalloproteinase inhibitor for the treatment of chronic wounds

Stability, activity, and application of topical doxycycline formulations in a diabetic wound case study

Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia

Ibuprofen as a template molecule for drug design against Ebola virus

Use of nonsteroidal antiinflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer

Comparative antiviral efficiency of leukocyte and bacterially produced human α-interferon in rhesus monkeys

Structure and Expression of Human Alpha-interferon Genes. Interferons. 25

Structure and expression of human IFN-alpha genes

Recent advances in antiviral interferon-stimulated gene biology

Pegylated interferon alpha 2a for the treatment of hepatitis C virus infection

Sustained antiviral effects and clearance of hepatitis surface antigen after combination therapy with entecavir and pegylated interferon in chronic hepatitis B

An orally available, small-molecule interferon inhibits viral replication

The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulates an antiviral state and protects mice against herpes simplex virus-induced neurological disease

STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice

HBV bypasses the innate immune response and does not protect HCV from antiviral activity of interferon

Vaccinia virus C9 ankyrin repeat/F-box protein is a newly identified antagonist of the type I interferoninduced antiviral state

Respiratory syncytial virus activates epidermal growth factor receptor to suppress interferon regulatory factor 1-dependent interferon-lambda and antiviral defense in airway epithelium

Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein

Biological and targeted therapies of systemic lupus erythematosus: evidence and the state of the art

Association of serum interferon-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents

Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis?

Structural basis of the broadly neutralizing anti-interferon-α antibody rontalizumab: neutralizing anti-interferon-α antibody rontalizumab

Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study

Hypomethylation ofSTAT1andHLA-DRB1is associated with type-I interferon-dependentHLA-DRB1expression in lupus CD8+ T cells

Assessment of clinical response to janus kinase inhibition in patients with familial chilblain lupus and TREX1 mutation

JAK-STAT signaling pathway inhibition: a role for treatment of discoid lupus erythematosus and dermatomyositis

Demarcation of viral shelters results in destruction by membranolytic GTPases: antiviral function of autophagy proteins and interferon-inducible GTPases

A new mechanism of interferon's antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene

Zika virus infection activates sting-dependent antiviral autophagy in the Drosophila brain

Antiviral and antiinflammatory activity of budesonide against human rhinovirus infection mediated via autophagy activation

The exoribonuclease Xrn1 is a post-transcriptional negative regulator of autophagy

Inhibition of cellular autophagy deranges dengue virion maturation

Polyglutamine repeats in viruses

PI3K-Akt-mTOR axis sustains rotavirus infection via the 4E-BP1 mediated autophagy pathway and represents an antiviral target

In vitro and in vivo activity of amiodarone against Ebola virus

Screening of FDA-approved drugs for inhibitors of Japanese Encephalitis virus infection

Repurposing the clinically approved calcium antagonist manidipine dihydrochloride as a new early inhibitor of human cytomegalovirus targeting the Immediate-Early 2 (IE2) protein

Screening and Identification of Lassa virus entry inhibitors from an FDA-approved drug library

A high-throughput flow cytometry screen identifies molecules that inhibit hantavirus cell entry

Handbook of clinical neurology

Giving drugs a second chance: overcoming regulatory and financial hurdles in repurposing approved drugs as cancer therapeutics

Safety and efficacy of rose bengal derivatives for glial scar ablation in chronic spinal cord injury

Intralesional PV-10 for the treatment of in-transit melanoma metastases-results of a prospective, nonrandomized, single center study

Post-HTS case report and structural alert: promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR

Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing

Seven year itch: Pan-Assay Interference Compounds (PAINS) in 2017-utility and limitations

Novel Paul A. structure-based mechanism for uridylylation of the genome-linked peptide (VPg) of picornaviruses

NMR solution structure of poliovirus uridylyated peptide linked to the genome (VPgpU)

Sequence specificity for uridylylation of the viral peptide linked to the genome (VPg) of enteroviruses

Allosteric inhibitors of Coxsackie virus A24 RNA polymerase

ZINC 15-ligand discovery for everyone

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information

Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the antiprotozoan drug emetine. eLife

Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations

How do the alkaloids emetine and homoharringtonine kill trypanosomes? An insight into their molecular modes of action

A rapid, high-throughput viability assay for Blastocystis spp. reveals metronidazole resistance and extensive subtype-dependent variations in drug susceptibilities

Isolation of emetine resistant clones of Entamoeba histolytica by petri dish agar method

Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells

High-Throughput minigenome system for identifying small-molecule inhibitors of ebola virus replication

Calcineurin-NFAT signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy

Cell-based high-throughput screening assay identifies 2′,2′-difluoro-2′-deoxycytidine gemcitabine as a potential antipoliovirus agent

Gemcitabine, a broad-spectrum antiviral drug, suppresses enterovirus infections through innate immunity induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion

Repurposing of rutin for the inhibition of norovirus replication

Drug repurposing of quinine as antiviral against dengue virus infection

Amodiaquine, an antimalarial drug, inhibits dengue virus type 2 replication and infectivity

The antimalarial drug amodiaquine possesses anti-ZIKA virus activities

Middle east respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies

Investigating drug repositioning opportunities in FDA drug labels through topic modeling

The recognition of identical ligands by unrelated proteins

In vitro and in vivo activities of antiinfluenza virus compound T-705

Distinct effects of T-705 (Favipiravir) and Ribavirin on Influenza virus replication and viral RNA synthesis

Favipiravir (T-705), a novel viral RNA polymerase inhibitor

T-705), a broad spectrum inhibitor of viral RNA polymerase

Enhanced protection against experimental Junin virus infection through the use of a modified favipiravir loading dose strategy

Favipiravir (T-705) but not ribavirin is effective against two distinct strains of Crimean-Congo hemorrhagic fever virus in mice

Dose regimen of favipiravir for Ebola virus disease

Antiviral efficacy of favipiravir against Ebola virus: a translational study in cynomolgus macaques

Use of favipiravir to treat Lassa virus infection in Macaques

Favipiravir and Ribavirin treatment of epidemiologically linked cases of Lassa fever

Combination therapy with oseltamivir and favipiravir delays mortality but does not prevent oseltamivir resistance in immunodeficient mice infected with pandemic A (H1N1) Influenza virus

Favipiravir pharmacokinetics in Ebola-infected patients of the JIKI trial reveals concentrations lower than targeted

Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir

Lending a helping hand, screening chemical libraries for compounds that enhance βhexosaminidase A activity in GM2 gangliosidosis cells: screening libraries for hexosaminidase enhancers

An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants)

Effect of cyclic, low dose pyrimethamine treatment in patients with late onset Tay Sachs: an open label, extended pilot study

Pyrimethamine derivatives: insight into binding mechanism and improved enhancement of mutant β-N-acetylhexosaminidase activity

Siderophore conjugates of daptomycin are potent inhibitors of carbapenem resistant strains of acinetobacter baumannii

Omadacycline enters the ring: a new antimicrobial contender

Review of eravacycline, a novel fluorocycline antibacterial agent

In-vitro activity of the novel fluorocycline eravacycline against carbapenem nonsusceptible Acinetobacter baumannii

Microbiological profile of sarecycline, a novel targeted spectrum tetracycline for the treatment of acne vulgaris

Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris: results from two identically designed, phase 3, randomized, double-blind clinical trials

Potential cost-savings with once-daily aminomethylcycline antibiotic versus vancomycin in hospitalized patients with acute bacterial skin and skin structure infections