Dipeptide-derived nitriles containing additional electrophilic sites: Potentially irreversible inhibitors of cysteine proteases

Löser, Reik; Gütschow, Michael

doi:10.3109/14756360902797328

Cited by 4 publications

(9 citation statements)

References 34 publications

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“…Mass spectra were recorded on an API 2000 mass spectrometer (electrospray ion source, Applied Biosystems, Darmstadt, Germany) coupled with an Agilent 1100 HPLC system using aP henomenex Luna HPLC C 18 column (50 2.00 mm, particle size: 3 mm). [19] (17):B oc-Leu-OH (1.12 g, 4.50 mmol) was dissolved in dry THF (20 mL) and cooled at À25 8C. Then, 10 mLoft he substance solution was injected into the Phenomenex Luna C 18 column, and elution was carried out with ag radient of H 2 O/MeOH containing 2mm ammonium acetate from 90:10 up to 0:100 for 30 min at af low rate of 250 mLmin À1 ,s tarting the gradient after 10 min.…”

Section: Methodsmentioning

confidence: 99%

“…[2,8,[13][14][15][16][17][18][19][20] The covalent reaction of peptiden itrilesw ithc ysteine cathepsins involves attack of the active-site thiolate at the inhibitor's nitrile carbon atom and reversible formation of at hioimidate adduct (Scheme 1). Nitrilebased inhibitors can be designed by startingf rom the specific substrates tructure of the target cysteine protease by introducing an itrile group as reactivew arheadi np lace of the carbonyl group anda dditional peptidomimetic modifications.…”

Section: Introductionmentioning

confidence: 99%

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Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors

et al. 2015

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Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex class II. Cathepsin S is the major processing enzyme of the invariant chain, but cathepsin F acts in macrophages as its functional synergist which is as potent as cathepsin S in invariant chain cleavage. Dedicated low-molecular-weight inhibitors for cathepsin F have not yet been developed. An active site mapping with 52 dipeptide nitriles, reacting as covalent-reversible inhibitors, was performed to draw structure-activity relationships for the non-primed binding region of human cathepsin F. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsins F, B, L, K and S. Compounds 10 (N-(4-phenylbenzoyl)-leucylglycine nitrile) and 12 (N-(4-phenylbenzoyl)leucylmethionine nitrile) were found to be potent inhibitors of human cathepsin F, with Ki values <10 nM. With all dipeptide nitriles from our study, a 3D activity landscape was generated to visualize structure-activity relationships for this series of cathepsin F inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors

et al. 2015

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“…These molecules can be used as templates for the development of new inhibitors specific to individual plasmodial proteases [6]. One of the best studied plasmodial metabolic pathways is the process of haemoglobin degradation [7]. Within the intra-erythrocytic form of the parasite the haemoglobin is degraded by papain-like CPs (falcipains) and aspartic proteases (plasmepsins) to amino acids utilized by the parasite to grow and replicate [7].…”

Section: Protease Inhibitorsmentioning

confidence: 99%

“…One of the best studied plasmodial metabolic pathways is the process of haemoglobin degradation [7]. Within the intra-erythrocytic form of the parasite the haemoglobin is degraded by papain-like CPs (falcipains) and aspartic proteases (plasmepsins) to amino acids utilized by the parasite to grow and replicate [7]. The P. falciparum falcipains involved in haemoglobin catabolism (falcipain-2, falcipain-2’, and falcipain 3) are recognized as promising targets of new antimalarial drugs [8].…”

Section: Protease Inhibitorsmentioning

confidence: 99%

“…The P. falciparum falcipains involved in haemoglobin catabolism (falcipain-2, falcipain-2’, and falcipain 3) are recognized as promising targets of new antimalarial drugs [8]. Some compounds of the azadipeptide nitrile family display in vitro structure-dependent antimalarial activity against both chloroquine-sensitive and chloroquine resistant P. falciparum by inhibiting falcipain 2 and 3 [7]. Malaria plasmepsins are responsible for the initial cleavage of haemoglobin within the food vacuole of the parasite during its erythrocytic stage.…”

Section: Protease Inhibitorsmentioning

confidence: 99%

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Current Developments in the Therapy of Protozoan Infections

Zucca

Savoia²

2011

Open Med Chem J

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Protozoan parasites cause serious human and zoonotic infections, including life-threatening diseases such as malaria, African and American trypanosomiasis, and leishmaniasis. These diseases are no more common in the developed world, but together they still threaten about 40% of the world population (WHO estimates). Mortality and morbidity are high in developing countries, and the lack of vaccines makes chemotherapy the only suitable option. However, available antiparasitic drugs are hampered by more or less marked toxic side effects and by the emergence of drug resistance. As the main prevalence of parasitic diseases occurs in the poorest areas of the world, the interest of the pharmaceutical companies in the development of new drugs has been traditionally scarce. The establishment of public-private partnerships focused on tropical diseases is changing this situation, allowing the exploitation of the technological advances that took place during the past decade related to genomics, proteomics, and in silico drug discovery approaches. These techniques allowed the identification of new molecular targets that in some cases are shared by different parasites. In this review we outline the recent developments in the fields of protease and topoisomerase inhibitors, antimicrobial and cell-penetrating peptides, and RNA interference. We also report on the rapidly developing field of new vectors (micro and nano particles, mesoporous materials) that in some cases can cross host or parasite natural barriers and, by selectively delivering new or already in use drugs to the target site, minimize dosage and side effects.

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Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain

et al. 2022

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The monomeric catalytic domain (residues 1–199) of SARS-CoV-2 main protease (MPro1-199) fused to 25 amino acids of its flanking nsp4 region mediates its autoprocessing at the nsp4-MPro1-199 junction. We report the catalytic activity and the dissociation constants of MPro1-199 and its analogs with the covalent inhibitors GC373 and nirmatrelvir (NMV), and the estimated monomer-dimer equilibrium constants of these complexes. Mass spectrometry indicates the presence of the accumulated adduct of NMV bound to MProWT and MPro1-199 and not of GC373. A room temperature crystal structure reveals a native-like fold of the catalytic domain with an unwound oxyanion loop (E state). In contrast, the structure of a covalent complex of the catalytic domain-GC373 or NMV shows an oxyanion loop conformation (E* state) resembling the full-length mature dimer. These results suggest that the E-E* equilibrium modulates autoprocessing of the main protease when converting from a monomeric polyprotein precursor to the mature dimer.

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Dipeptide-derived nitriles containing additional electrophilic sites: Potentially irreversible inhibitors of cysteine proteases

Cited by 4 publications

References 34 publications

Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors

Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors

Current Developments in the Therapy of Protozoan Infections

Autoprocessing and oxyanion loop reorganization upon GC373 and nirmatrelvir binding of monomeric SARS-CoV-2 main protease catalytic domain

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