Cathepsin B: Active site mapping with peptidic substrates and inhibitors

Schmitz, Janina; Gilberg, Erik; Löser, Reik; Bajorath, Jürgen; Bartz, Ulrike; Gütschow, Michael

doi:10.1016/j.bmc.2018.10.017

Cited by 54 publications

(51 citation statements)

References 104 publications

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“…A variety of studies have been conducted on optimization strategies for the interactions of different classes of inhibitors with the S1, S2 and S3 binding sites of cruzain and related cysteine proteases [13,14,19,20]. Nonetheless, far less is known about the attainable interactions at S1′ for dipeptidyl nitrile inhibitors [21].…”

Section: Resultsmentioning

confidence: 99%

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

Cianni¹,

Lemke²,

Gilberg³

et al. 2019

Preprint

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26The cysteine protease cruzipain is considered to be a validated target for therapeutic 27 intervention in the treatment of Chagas disease. A series of 26 new compounds 28 waswere designed, synthesized, and tested against the recombinant cruzain (Cz) to 29 map its S1/S1´ subsites. The same series was evaluated on a panel of four human 30 cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which 31 is a potential target for the treatment of cutaneous leishmaniasis. The synthesized 32 compounds are dipeptidyl nitriles designed based on the most promising 33 combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building 34 blocks). Eight compounds exhibited a K i smaller than 20.0 nM for Cz, whereas three 35 compounds met these criteria for LmCPB. The three inhibitors had an EC 50 value of 36 ca. 4 μM, thus being equipotent to benznidazole according to the anti-trypanosomal 37 effects. Our mapping approach and the respective structure-activity relationships 38 provide insights into the specific ligand-target interactions for therapeutically relevant 39 cysteine proteases. 40 41 Author Summary 42 43 Despite many achievements in identifying novel agents for the treatment of tropical 44 and neglected diseases, further research continues to be of fundamental importance.45 Our research groups have been using the cruzipain cysteine protease in its 46 recombinant form, cruzain (Cz), to identify new trypanocidal agents. Considering the 47 50 different disease states. Thus, the inhibitors were also tested against cathepsins B, 51 L, K, and S. Our results demonstrate that inhibition of these cysteine proteases can 52 be achieved by appropriate structural modifications of dipeptidyl nitriles. It was also 53 possible to identify trypanocidal agents, equipotent to benznidazole, the current drug 54 of choice used for the treatment of Chagas disease. 55 56 57 Chagas disease, aka American trypanosomiasis, is a serious health and social 58 problem in Latin America and new non-endemic areas such as Japan, East Europe, 59 and the USA. Chagas disease has an annual incidence of 30,000 new cases and 60 14,000 deaths per year. In addition, more than 70,000 million people living in areas 61 where they are at risk of contracting the disease [1]. 62 The etiological agent, the protozoa parasite Trypanosoma cruzi (T. cruzi), is 63 transmitted by blood-sucking reduviid bugs of the subfamily Triatominae [2]. The only 64 two existing drugs in the market, benznidazole and nifurtimox, show strong side 65 effects and inefficiency in the chronic stage of the disease [3,4]. New safe and 66 efficacious drugs are therefore required to address with these still unmet medical 67 needs. Initiatives such as the one launched by the Drugs for Neglected Diseases 68 (DNDi) have led to worldwide collaborative efforts to discover new therapeutic 69 targets [5]. Cruzain (Cz), a recombinant form of the enzyme cruzipain (EC 3.4.22.51) 70 [6], is the most abundant cysteine protease (CP) present in the parasite and 7...

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Section: Resultsmentioning

confidence: 99%

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

Cianni¹,

Lemke²,

Gilberg³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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“…In tumor therapy experiments with ADCs in vivo, this new linker displayed superior therapeutic activity than the traditional Val‐Cit, even when the linker was further exposed to enzymatic degradation by insertion of a PEG spacer between the linker and the mAb structure . While the Glu‐Val‐Cit linker represents a successful example of improved drug release specificity by hindering the enzymatic action of competitor enzymes, another logical strategy is to exploit available crystallographic data to tailor the linker structure and enhance the specificity towards the enzyme of interest . This goal was recently pursued by Genentech, with the replacement of the Val residue in the Val‐Cit dipeptide with a cyclobutane‐1,1‐dicarboxamide moiety (i.e.…”

Section: Exploiting the Hallmarks Of Cancer: Linker Cleavage Promotedmentioning

confidence: 99%

“…[28] While the Glu-Val-Cit linker represents as uccessful example of improved drug release specificityb yh indering the enzymatic action of competitor enzymes, another logical strategy is to exploit available crystallographic data to tailor the linker structure ande nhancet he specificityt owards the enzyme of interest. [29] This goal was recently pursued by Genentech, with the replacement of the Valr esidue in the Val-Cit dipeptidew ithacyclobutane-1,1dicarboxamide moiety (i.e. cBu-Citl inker 3,S cheme 1).…”

Section: Carrier + + Drug + + Linkermentioning

confidence: 99%

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

Corso

Pignataro

Belvisi

et al. 2019

Chemistry A European J

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The covalent conjugation of potent cytotoxic agents to either macromolecular carriers or small molecules represents a well‐known approach to increase the therapeutic index of these drugs, thus improving treatment efficacy and minimizing side effects. In general, cytotoxic activity is displayed only upon cleavage of a specific chemical bond (linker) that connects the drug to the carrier. The perfect balance between the linker stability and its selective cleavage represents the key for success in these therapeutic approaches and the chemical toolbox to reach this goal is continuously expanding. In this Review article, we highlight recent advances on the different modalities to promote the selective release of cytotoxic agents, either by exploiting specific hallmarks of the tumor microenvironment (e.g. pH, enzyme expression) or by the application of external triggers (e.g. light and bioorthogonal reactions).

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“…A variety of studies have been conducted on optimization strategies for the interactions of different classes of inhibitors with the S1, S2 and S3 binding sites of cruzain and related cysteine proteases [12,14,15,20]. Nonetheless, far less is known about the attainable interactions at S1 0 for dipeptidyl nitrile inhibitors [21].…”

Section: Structure-based Design Modeling Studies and Compound Synthmentioning

confidence: 99%

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

et al. 2020

Self Cite

View full text Add to dashboard Cite

The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1ś ubsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a K i smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC 50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.

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Cathepsin B: Active site mapping with peptidic substrates and inhibitors

Cited by 54 publications

References 104 publications

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

Innovative Linker Strategies for Tumor‐Targeted Drug Conjugates

Mapping the S1 and S1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents

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