3-Cyano-3-aza-β-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins

Schmitz, Janina; Beckmann, Anna-Madeleine; Dudic, Adela; Li, Tianwei; Sellier, Robert; Bartz, Ulrike; Gütschow, Michael

doi:10.1021/ml500238q

Cited by 15 publications

(20 citation statements)

References 35 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]. The high-resolution crystal structure of cruzain shows that there is a large open surface characterized by Trp177 in the primed binding site region (Fig 3) [22].…”

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

show abstract

“…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]. The high-resolution crystal structure of cruzain shows that there is a large open surface characterized by Trp177 in the primed binding site region (Fig 3) [22].…”

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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“…Based on the significance of nitrile type inhibitors aza dipeptide nitriles have been introduced as a new class of inhibitors [63]. Further, the chemo type of 3-cyano-3-aza-β-amino acid derivatives was designed in which the N-cyano group is centrally arranged to allow for interaction with the unprimed and primed binding regions of cathepsin K [64].…”

Section: Various Azapeptide Scaffolds As Peptidomimeticsmentioning

confidence: 99%

A Review on Azapeptides: The Promising Peptidomimetics

Begum¹,

Sujatha²,

Prasad³

et al. 2017

Asian J. Chem.

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Peptidomimetics, the mimics of natural peptides are considered as promising therapeutics with potential applications in modern medicine. Among the various structural variants of peptidomimetics that have been designed and synthesized, the azapeptides serve as the interesting peptide backbone modifications owing to their diversified biological and pharmacokinetic properties. The aim of this review is to highlight the significance of azapeptide in enhancement of stability and bioavailability, represent the various scaffolds of azapeptides as peptidomimetics, notify their significance as cysteine and serine protease inhibitors, provide an insight on the various biologically significant azapeptides and emphasize the main features on the conventional to modified synthetic strategies of azapeptides.

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3-Cyano-3-aza-β-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins

Cited by 15 publications

References 35 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

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

A Review on Azapeptides: The Promising Peptidomimetics

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