Suicide inhibitors

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  • SUICIDEINHIBITORSGuided byDr. V. M. Motghare Dr. Swarnank ParmarJR-1Dept. Of PharmacologyGMC Nagpur

  • Overview IntroductionTypes of InhibitionSuicide inhibitorsClinical examplesConclusionReferences

  • Introduction Suicide inhibition, also known as suicide inactivation, is a form of irreversible enzyme inhibition that occurs when an enzyme binds a substrate analogue and forms an irreversible complex with it through a covalent bond during the "normal" catalysis reaction

  • Inhibitor binds to active site where it is modified by the enzyme to produce a reactive group that reacts irreversibly to form a stable inhibitor-enzyme complex

    Inhibitor has a functional group, usually a leaving group, that is replaced by a nucleophile in the enzyme active site

    Reaction with suicide inhibitor removes active enzyme from the system; this removal is measured as inhibition

  • ReversibleIrreversibleType of InhibitorsCompetitiveUncompetitiveNon- CompetitiveActive Site DirectedSuicideInhibitors

  • A special group of irreversible inhibitors is known as suicide inhibitors

    A suicide inhibitor is a relatively inert molecule that is transformed by an enzyme at its active site into a reactive compound that irreversibly inactivates the enzyme

    Relatively unreactive until they bind to the active site of the enzyme

    Suicide Inhibitors

  • First few steps of the reaction it functions like a normal substrate, but then it is converted into a very reactive compound that combines with the enzyme to block its activity

    They use the normal enzyme reaction mechanism to inactivate the enzyme, they are also known as mechanism-based inhibitors or transition state analogs

  • Suicide inhibitors that exploit the transition state-stabilizing effect of the enzyme result in higher enzyme binding affinity than do substrate-based inhibitor designs

    Designing drugs that precisely mimic the transition state is a real challenge because of the unstable, poorly characterized structure of the transition state

  • Prodrugs undergo one or more initial reactions to form an overall electrostatic and three-dimensional intermediate transition state complex form with close similarity to that of the substrate

    Serves as guidelines to further develop transition state molecules with modifications

    Such inhibitors are called suicide inhibitors because the enzyme appears to commit suicide

  • A common example of a suicide inhibitor is Allopurinol, the anti-gout drug that inhibits xanthine oxidase activity. The enzyme commits suicide by initially activating Allopurinol into Oxypurinol (a transition state analog) that binds very tightly to the molybdenum-sulfide (Mo-S) complex at the active site of xanthine oxidase

  • Acyclovir is one of the most commonly used antiviral agents with very low toxicity. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase

    Acyclo-GMP is further phosphorylated into the active triphosphate form, acyclo-GTP, by cellular kinases

  • Acyclo-GTP is a very potent inhibitor of viral DNA polymerase with over 100-fold greater affinity for viral than cellular polymerase.

    It is incorporated into viral DNA, resulting in chain termination

    The suicide inhibitor removes enzyme and reduces the formation of ES complex. The Vmax value is reduced and inhibition cannot be overcome by adding extra substrate. In this regard, suicide inhibition resembles non-competitive inhibition

  • Some clinical examples of suicide inhibitors

    5-fluorouracilacts as a suicide inhibitor of thymidylate synthase during the synthesis of thymine from uridine

    Reaction is crucial for proliferation of cells, particularly those that are rapidly proliferating (such as fast-growing cancer tumors)

  • During thymidylate synthesis, N5,N10- methyleneTHF is converted to 7,8-dihydrofolate; methyleneTHF is regenerated in two steps

  • Inhibition causes cell death from lack ofthymine to create more DNA

    This is often used in combination withMethotrexate, a potent inhibitor ofdihydrofolate reductaseenzyme

  • Aspirin, which inhibits cyclooxygenase- Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2

  • Low doses of aspirin (75mg-81mg/day) sufficient to irreversibly acetylate serine530 of COX-1

    Inhibits platelets generation of TXA2 antithrombin effect

    Intermediate doses (650mg-4g/day) inhibit COX-1 & COX-2 blocking PG production

  • Penicillin, which inhibitsDD-transpeptidasefrom building bacterialcell walls- Penicillin blocks the formation of the cross-link between the N-acetylmuramic acid and N-acetylglucosamine

  • Benzothiazinones (BTZs) - antituberculosis drug, are suicide substrates of the FAD-dependent decaprenylphosphoryl--D-ribofuranose 2'-oxidase DprE1, an enzyme involved in cell-wall biogenesis

    Serine proteases are attractive targets for the design of enzyme inhibitors

    Within the class of serine proteases, Human Leucocyte Elastase(HLE) is one of the most destructive enzymes in the body

  • Numerous inhibitors of serine proteases reported during the past three decades

    Coumarin-type molecules displayed high inhibitory potency towards various serine proteases

    Halomethyl dihydrocoumarins - shown to behave as the first general suicide inhibitors of serine protease

    Inhibit several proteases - human leucocyte elastase, porcine pancreatic elastase, thrombin, urokinase and human plasmin

  • Series of mechanism-based inhibitors of Phospholipase A2 (SIBLINKS) were synthesized

    Phospholipid analogues that contain a para-substituted phenyl 3,3-dimethylglutaryl group in the place of the sn-2 acyl chain

  • Effect of the phenyl leaving group on inhibitory activity was studied by varying electron-withdrawing ability of the para-substituted group

    Strong correlation observed between leaving group potential of suicide inhibitor and inhibitory activity of the derivative toward cobra venom phospholipase A2.

  • TCAs act primarily asserotonin-norepinephrine reuptake inhibitors(SNRIs)

    Blocks serotonin transporter (SERT) and nor-epinephrine transporter (NET)-elevation of the synaptic concentrations of neurotransmitters

    Clavulanic acid is asuicide inhibitor, covalently bonding to aserineresidue in theactive siteof the -Lactamase

  • Restructures clavulanic acid molecule, creating a more reactive species - attacked by another amino acid in the active site, permanently inactivating the enzyme

    This inhibition restores the antimicrobial activity of -lactam antibiotics against lactamase-secreting resistant bacteria

  • AZT(zidovudine) and other chain-terminating nucleosideanalogues used to selectively inhibit HIV-1 reverse transcriptasein the treatment ofHIV/AIDS

    Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrateandrostenedione binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as suicide inhibition

  • Sulbactum is an irreversible inhibitor of lactamase, which prohibits penicillin-resistant strains of bacteria from metabolizing penicillin

    Sarin (Organophosphorus compound)is a potent suicide inhibitor ofacetylcholinesterase degrading neurotransmitter Acetylcholine after its release

    Benzotriazole esters(used in SARS) reported as potent nonpeptidic suicide inhibitors of the enzyme proteinase, acts at active-site cysteine, acylated by benzotriazole esters

  • Selegiline (selective irreversible MAO-B inhibitor) although in the attached reference the compound is called a 'suicide inactivator' (not inhibitor)

  • Serpinsare a group ofproteinswith similar structures that were first identified as a set of proteins able toinhibitproteases

    Serpins are suicide inhibitors

    Serpin1 ofArabidopsis thalianais a Suicide Inhibitor for Metacaspase 9

    Serpins are referred to as suicide inhibitors because they are cleaved by their target proteases

  • Vigabatrin, ananticonvulsantis a irreversible suicide inhibitor ofGABA-Transaminase (responsible for catabolism of GABA) increasing level of GABA in brain

    -haloamines represent a new series of suicide inhibitors of lysyl oxidase which can inactivate the enzyme faster than BAPN (-aminoproprionitrile) and may have antifibrotic potential

  • Plasminogen activator inhibitor-1(PAI-1), representative of the serpin superfamily is the major regulator of tissue-type (tPA) and urokinase-type (uPA) plasminogen activators in vivo

    PAI-1 plays a role in the control of normal fibrinolysis as well as a number of physiological processes that are dependent on plasminogen activation

  • PAI-1 acts as a suicide inhibitor that inactivates target proteinases by trapping a stabilized acyl enzyme intermediate

    Significant structural changes accompanying the reaction result in efficient and essentially irreversible impairment of the proteinase mechanism

  • Eflornithine, one of the drugs used to treatsleeping sickness, is a suicide inhibitor ofOrnithine Decarboxylase(ODC) preventing the natural substrate Ornithine from accessing the active site

    DFMO (difluoromethylornithine) and DFMA (difluoromethylarginine), irreversible suicide inhibitors of ornithine and arginine decarboxylase activities (ODC and ADC) respectively

    Inhibit the growth of six species of Microsporumand six species ofTrichophyton

  • Hit and Run drugsAre the drugs whose effect lasts much longer than the drug itselfBecause, drug with a relatively short t still able to produce effe