Drug Repurposing for Emerging Infectious Diseases and Cancer

664 Pages·2023·14.217 MB·English

by  Ranbir Chander Sobti, Sunil K. Lal, Ramesh K. Goyal

Drug Repurposing
for Emerging Infectious
Diseases and Cancer
Ranbir Chander Sobti
Sunil K. Lal
Ramesh K. Goyal
Editors
Drug Repurposing for Emerging Infectious Diseases
and Cancer
(cid:129) (cid:129)
Ranbir Chander Sobti Sunil K. Lal
Ramesh K. Goyal
Editors
Drug Repurposing
for Emerging Infectious
Diseases and Cancer
Editors
RanbirChanderSobti SunilK.Lal
DepartmentofBiotechnology SchoolofScience
PanjabUniversity MonashUniversityMalaysia
Chandigarh,Chandigarh,India BandarSunway,Selangor,Malaysia
RameshK.Goyal
DelhiPharmaceuticalSciencesand
Research
NewDelhi,India
ISBN978-981-19-5398-9 ISBN978-981-19-5399-6 (eBook)
https://doi.org/10.1007/978-981-19-5399-6
©TheEditor(s)(ifapplicable)andTheAuthor(s),underexclusivelicensetoSpringerNatureSingapore
PteLtd.2023
Thisworkissubjecttocopyright.AllrightsaresolelyandexclusivelylicensedbythePublisher,whether
thewholeorpartofthematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseof
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by
similarordissimilarmethodologynowknownorhereafterdeveloped.
Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication
doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant
protectivelawsandregulationsandthereforefreeforgeneraluse.
The publisher, the authors, and the editorsare safeto assume that the adviceand informationin this
bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor
theeditorsgiveawarranty,expressedorimplied,withrespecttothematerialcontainedhereinorforany
errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional
claimsinpublishedmapsandinstitutionalaffiliations.
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
Preface
Medicines have always been discovered and invented with desired and intended
purposes and consequences. With deeper understandings, we are able to discover
many more facets about these drugs. In mid-1900s when mercaptopurine was
introduced,thescientistsdidencounteritsassociationwithalife-threateningcondi-
tion of bone-marrow toxicity. Similarly in 1950s, another drug succinylcholine, a
muscle relaxant, has been associated with respiratory distress.1 These are both the
horrifying conditions of adverse reactions. But these certainly paved the way not
only for efficacy of desired drug response but also for the off-target effects of the
drugs.
These off-targets do provide a clue about the pharmacodynamic effect of the
drugs, i.e., what a particular drug does to the body or what are the biochemical,
physiological,andmoleculareffectsofthedrug.Thisactuallyprovidedamajorclue
thatifallthebiologicaltargetsarerevealedthereisaprovisionofreconsiderationof
any drug for alternate purpose. This phenomenon has been termed as the drug
repurposingwhichcanbeexploitedinthetreatmentofvariousappallingconditions
inatimeandcost-effectivemanner.Thisreprofilingapproachfordrugsalsoprovide
a way out from traditional method of drug discovery which besides being very
expensive($1.6billion/drug)arealsotimeconsuming(~10–15years).Moreover,a
constant decline in the FDA approval of new drugs especially in the field of
oncologynecessitatednovelapproachestoexpeditetheprocessofdrugdiscovery.
Drugrepurposingisestablishmentofnewmedicalusesforalreadyknowndrugs.
Therepositioningofanactivepharmaceuticalingredientthatisalreadyavailablein
the market for a new indication is referred to as drug repurposing. Several
repositioned drugs, including some very old drugs, have been used throughout the
course of medicine historically. This repositioning of drugs was purely through
serendipity in those times. In the present scenario, novel methods based on data
1Bourne JG,Longactionofsuxamethonium (succinylcholine) chloride.Br JAnaesth 1953:25;
116–29.
v
vi Preface
mining have been developed for identification of new candidates for drug
repurposing. The success of drug repositioning in providing benefits in certain
diseases brought the global attention on the potential off-target effects of some of
thedrugs.Inviewofthefactthattheseexistingdrugshavebeenusedpreviouslyin
humans,theirdoseregimenwithfavourablepharmacokineticsandpharmacodynam-
icspropertiesincludinganysideeffectsarealreadyinpublicdomain,makingthese
olddrugsusefulinnewdrugdiscovery.
The“repurposing”ofexistingtherapiesforalternativediseaseavoidslongregu-
latoryprocesses,funds,andintellectualpropertyright.Itisgainingpopularityasan
approach to identify new targets of medicines in use. Researchers from Case
WesternReserveUniversity School of Medicine and collaborators havereceived a
five-year, $2.8 million grant from the National Institute on Aging to identify
FDA-approved medications that could be repurposed to treat Alzheimer's disease.
Bedaquiline—new anti-TB drug for treating drug-resistant TB has identified using
the principle of repurposing of existing drugs. Celecoxib, a non-steroidal anti-
inflammatorydrug (NSAID) has demonstratedantibacterial activity bycausingthe
inhibitionofDNAandRNAreplication,proteinsynthesis,andcellwallformation,
whilesimultaneouslyreducingthelevelsofIL-6,TNF-α,IL-1β,andMCP-1(mono-
cyte-chemoattractant protein-1) against various pathogens including S. aureus,
Bacillus anthracis, B. subtilis, and M. smegmatis. With the exception of linezolid,
celecoxibhasalsodemonstratedsynergisticeffectswithseveraltopicalandsystemic
antimicrobialsusedagainstS.aureus.Alsoantidiabeticdrugmetformin(MET)has
been reported to inhibit the intracellular growth of mycobacteria. Quinine, could
slow the growth of Candida species. Drugs used for obesity treatment (lipase
inhibitors) and Cyclipostins and Cyclophostin analogs were reported as promising
compounds in the fight against tuberculosis. It targets several serine or cysteine
enzymes involved in M.tb lipid metabolism and/or in cell wall biosynthesis. Lead
compoundsexhibitednanomolarinhibitionoftheenzyme,supportingRv3802casa
novelTBdrugtarget.Ithasdemonstratedencouragingantibacterialactivityagainst
M. tuberculosis in vitro. Itraconazole, a triazole antifungal drug, has demonstrated
anti-angiogenic property that lead to its usage either alone or in combination with
other anticancer drugs in various preclinical models including medulloblastoma,
non-small cell lung cancer (NSCLC), and basal cell carcinoma Digoxin, a cardiac
glycosideisolatedfromfoxgloveandusedfortreatingheartfailureandarrhythmia,
demonstrated glycoside triggered immunogenic demise of the cancer cells
Nitroxoline, an antibiotic, recently demonstrated the anticancer activity in prostate
cancer.Rituximab,usedtotreatrheumatoidarthritis,demonstratedanticanceractiv-
ityagainstseveralcancers.
Drugs used for obesity treatment (lipase inhibitors) and Cyclipostins and
Cyclophostin analogs have been reported as promising compounds in the fight
against tuberculosis. It targeted several serine or cysteine enzymes involved in M.
tblipidmetabolismand/orincellwallbiosynthesis.Itraconazole,atriazoleantifun-
galdrughasdemonstratedanti-angiogenicpropertythatleadtoitsusageeitheralone
orincombinationwithotheranticancerdrugsinvariouspreclinicalmodelsinclud-
ing medulloblastoma, non-small cell lung cancer (NSCLC), and basal cell
Preface vii
carcinoma. The major challenge faced by the institutes working on drug
repositioning is the relatively weak intellectual property protection on these prod-
ucts,whichcanleadtoreductioninreturnontheirinvestmentfurtherdiscouraging
thesecompaniesfromdevelopingthesedrugs.
The major challenge is how to reveal all the biological targets and avoid the
adversereactions.Variousapproachesfordrugrepurposing,coveringalltheaspects
arebeingpursuedindrugrepurposingdirectionandareasfollows.
Ligand-Basedapproaches:
(i) Library containing the FDA-approved drugs is tested by High-Throughput
screeningandstatisticallyevaluated.
(ii) VirtuallibraryofFDA-approveddrugsistestedbyReverseDockingtovarious
targets.
Target-BasedApproaches:
(i) Targetsareidentifiedandscreenedvirtuallydockingtolibraryofligands.
In both these approaches, the computational biology is being used as the prime
technologies followed by validation under in vitro or in vivo system. In case of
oncologyrepurposingsomeofthenotedexamplesareisoprenaline,anon-selective
β-adrenergic agonist exhibiting cytotoxic potential and fludarabine (purine ana-
logue) for chronic lymphocytic leukaemia. More recently, the use of chloroquin,
anantimalarialfortheinterventionofcovid-19virusreaffirmedtheneedtolookfor
thisaspectforthefuturistictherapeuticinterventions.
TheserepurposedtherapiesoffergreatadvantageastheirFDAapprovals,adverse
drug reportings (ADR), and therapeutic safe doses (TSD) are already determined.
Hence in the current scenario, in-depth study of ligand and targets offer great new
possibilitiesforrepurposeddrugs.
In the backdrop of all these, it is purposed to compile a book entitled Drug
RepurposingforEmergingInfectiousDiseasesandCancer.
Treatmentsofdiseasesthatareeitherrare,complex,ornovelmaynotalwaysbe
availableduetohighcostofdrugdevelopmentandresearch.Drugrepurposingisan
alternativeapproachtousurpalreadyavailabledrugsordrugcandidateswithFDA
approval which have been initially developed for specific diseases and re-establish
theiruseforotherdiseases.Moderngenomicmethodsfordrugrepurposinginvolve
the usage of computational programs and online tools to analyse and ultimately
deducetargetswithhighspecificitytobeconsideredascandidatesforrepositioning.
Gene, protein, disease, and drug databases are built from high-throughput experi-
mental, in vitro, in vivo, and clinical data thus providing a reliable basis for drug
target acquisition purposes. Key experimental and in silico approaches for modern
drugrepositioning, namely, signature matching, moleculardocking,genome-wide-
associatedstudies,andnetwork-basedapproachesaidedbyartificialintelligencewill
be described in this book, along with research examples that have used these
methods.
Drug repositioning for certain diseases such as Alzheimer’s disease, cystic
fibrosis, and SARS-CoV-2 disease will be discussed in separate sections of this
viii Preface
book. This book will highlight the challenges faced and the future perspectives of
Drug Repurposing. Genomic computational approaches for drug repurposing pre-
sentmuchpotentialinidentifyingdrugtargetsmoreefficientlyandeffectivelywhich
providestheopportunitytofulfilthegapforthetreatmentofdiseases with littleor
nocure.
Thecurrentpandemicofthecoronavirusdisease(COVID-19)andpasthistoryof
fast evolving emerging and re-emerging infectious diseases have put in place an
urgentneedfornewandpromisingantiviraltherapeutics.
Interestingly, there are many cellular pathways and biomolecules that serve as
keynodalpointsforbothcancerandinfectiousdiseaseprogression.Agoodexample
istheviralRNA-dependentRNApolymerase(RdRp)enzymethatplaysavitalrole
inviralreplicationofallRNAviruses,includingthecurrentSARS-CoV-2,thereby
makingitaprimeandpromisingcandidatefornovelantiviraltargeting.Thehuman
telomerase reverse transcriptase (hTERT), a common catalytic subunit of the telo-
merase enzyme in many cancers has also been identified with structural and func-
tionalsimilaritiestotheviralRdRp.Therefore,itbecomesimportanttoevaluateand
consider anticancer drugs that target hTERT for antiviral RdRp activity, and vice
versa. Forinstance,Floxuridine,anhTERTinhibitor,andVX-222,an HCVRdRp
inhibitor now being analysed as a potential antiviral for SARS-CoV-2 and anti-
hTERTforcancer,respectively.Inthisbook,weaimatbringingtolightthisclose
relationshipbetweenemerginginfectiousdiseasesandcancer.Weplantopunctuate
thisideawithspecificchaptersonthegreatpotentialofanticancerinhibitorsthatcan
be repurposed for infectious diseases. We all agree that cancer is a very studious
subject,andthereisavastamountofinformationoneffectivedrugsagainstvarious
cancers; however, there is very limited knowledge on the SARS-CoV-2 virus and
otherrecentemergingandre-emerginginfectiousdiseases.Hence,wefeelthisbook
will be a great contribution to science and will emerge as a major hot seller in the
field.
NewertechnologiesofOMICssubstantiatedbycomputationaltechniquesinclud-
ingartificialintelligence,etc.arebeingtriedforrediscoveryoffunctionalaspectsof
disease.
This book is a comprehensive volume on newer technologies as well as their
applications in drug discovery with up-to-date information on repurposed and
prospective drugs for cancer and infectious diseases with particular reference to
Covid-19.
RCS is thankful to the Indian National Science Academy, New Delhi, for
providingplatformasSeniorScientistandPanjabUniversity,Chandigarh,asEmer-
itus Professor to continue academic pursuits. He is thankful to his wife Dr Vipin
SobtianddaughtersAditiandAasthaandgranddaughterIrenebutfortheirsupportI
wouldnothavecompiledthebook.
Chandigarh,Punjab,India RanbirChanderSobti
BandarSunway,Selangor,Malaysia SunilK.Lal
NewDelhi,India RameshK.Goyal
Contents
1 DrugRepurposing:AnAdvanceWaytoTraditionalDrug
Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PriyaJoon,MiniDahiya,GarimaSharma,KritikaSharma,EupaRay,
MonikaKadian,RanbirChanderSobti,SanjeevPuri,andAnilKumar
2 DrugPolypharmacologyTowardDrugRepurposing. . . . . . . . . . . 27
TammannaR.Sahrawat,RitikaPatial,andRanbirChanderSobti
3 Pharmacovigilance-BasedDrugRepurposing. . . . . . . . . . . . . . . . . 37
PoojaGuptaandArchanaMishra
4 InSilicoAnalysisofCellularInteractorsofPQBP1forPotential
DrugRepurposing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
ShahKamranurRahman
5 DrugRepurposingOpportunitiesinCancer. . . . . . . . . . . . . . . . . . 53
PopatKumbhar,KapilKole,ArehalliManjappa,NirajKumarJha,
JohnDisouza,andVandanaPatravale
6 RepurposingofFlavonoidsasPromisingPhytochemicalsforthe
TreatmentofLungCarcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
VivekYadav,LovikaMittal,SwatiPaliwal,ShailendraAsthana,
andRajivK.Tonk
7 TargetedTherapiesUsedintheTreatmentofNon–Small-Cell
LungCancer:AnOverview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
TanujaYadav,VelishaMehta,NilamBhusare,MeenaChintamaneni,
andY.C.Mayur
8 DrugRepurposinginCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
N.R.Shruthi,M.SamathaJain,HarshaGanesan,AntaraBanerjee,
HongZhang,Xiao-FengSun,andSurajitPathak
ix
x Contents
9 TargetingtheUbiquitinMachineryforCancerTherapeutics. . . .. 181
JanviPatelandEktaTripathi
10 RepurposingofSerotoninPathwayInfluencingDrugsforPotential
CancerTherapyandAntimicrobialFunctions. . . . . . . . . . . . . . . . 203
MadhuryaRayandVipinKumar
11 DrugRepurposingforHematologicalMalignancies. . . . . . . . . . . . 217
AntonyAnistaMichael,PavithraBalakrishnan,
andThirunavukkarasuVelusamy
12 DrugRepurposingfor,ENTandHeadandNeck,Infectiousand
OncologicDiseases:CurrentPracticesandFuturePossibilities. . .. 253
SourabhaKumarPatro,NareshKumarPanda,andMaryadaSharma
13 RepurposingofImmunomodulatorsfortheTreatmentofCancer
withQSARApproaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
RajivK.Tonk,VivekYadav,andRameshK.Goyal
14 ReverseTranslationalApproachinRepurposingofDrugs
forAnticancerTherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
GeetaAggarwal,PankajMusyuni,BhartiMangla,
andRameshK.Goyal
15 TherapeuticTargetingofAntineoplasticDrugsinAlzheimer’s
Disease:DiscoveredinRepurposedAgents. . . . . . . . . . . . . . . . . . . 329
MiniDahiya,AnilKumar,MonuYadav,PratibhaDhakla,
andShivaTushir
16 RepurposingofDrugsfortheTreatmentofMicrobialDiseases. . . 347
KushalKumarBansal,RajatGoyal,ArchanaSharma,
PrabodhChanderSharma,andRameshK.Goyal
17 RepurposingAnti-inflammatoryAgentsinthePotentialTreatment
ofSARS-COV-2Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
AnsabAkhtar,JaspreetKaur,MeiNeeChiu,
andSangeetaPilkhwalSah
18 RepurposingDrugsforVirusesandCancer:ANovelDrug
RepositioningStrategyforCOVID-19. . . . . . . . . . . . . . . . . . . . . . . 423
KaHengWong,Chie-MinLim,AshleyJiaWenYip,
IsraAhmadFarouk,NurZawanahZabidi,ZhengYaoLow,
andSunilK.Lal
19 DrugRepurposingforCOVID-19Therapy:Pipeline,Current
StatusandChallenges. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
RohitVerma,ShivaniRaj,UmangBerry,C.T.Ranjith-Kumar,
andMilanSurjit