Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Cianni, Lorenzo; Rocho, Fernanda dos Reis; Bonatto, Vinícius; Martins, Felipe C.P.; Lameira, Jerônimo; Leitão, Andrei; Montanari, Carlos Alberto; Shamim, Anwar

doi:10.1016/j.bmc.2020.115827

Cited by 7 publications

(10 citation statements)

References 52 publications

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“…Our research group reported several peptidomimetic inhibitors of hCatL and other cysteine proteases in recent publications. ,,, These studies demonstrated that compounds bearing a halogen atom at the meta position of the P3 benzyl ring (Figure ) presented selectivity for hCatL over other CPs and showed a good affinity for the enzyme. Compounds with the biphenyl ring at P3 and related derivatives also exhibit a high affinity for hCatL.…”

Section: Results and Discussionmentioning

confidence: 98%

“…The synthesis, characterization, and enzymatic assays of compounds 1c , 1e , 2a , 2b , and 2c were previously reported . The synthesis of compounds 1a , 1b , and 1d was performed similarly, where the synthetic route was developed to optimize the placement of P1, P2, and P3 groups (see the Experimental Section in the Supporting Information for details).…”

Section: Methodsmentioning

confidence: 99%

“…In this work, eight nitrile-based inhibitors ( 1a–e and 2a–c ; see Figure ) were subjected to FEP analyses. Derivatives 1c , 1e , 2a , 2b , and 2c were previously reported, and compound 1c was used as a prototype for the synthesis of meta -halogenated molecular pairs coded 1a , 1b , and 1d , once halogen bonding in P3 was previously identified with Gly61 of hCatL . All ligands have the same scaffold but present differences in the terminal aromatic ring.…”

Section: Introductionmentioning

confidence: 99%

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Predicting the Relative Binding Affinity for Reversible Covalent Inhibitors by Free Energy Perturbation Calculations

Bonatto

Shamim

Rocho

et al. 2021

J. Chem. Inf. Model.

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Covalent inhibitors are assuming central importance in drug discovery projects, especially in this pandemic scenario. Many research groups have focused their attention on inhibiting viral proteases or human proteases such as cathepsin L (hCatL). The inhibition of these critical enzymes may impair viral replication. However, molecular modeling of covalent ligands is challenging since covalent and noncovalent ligand-bound states must be considered in the binding process. In this work, we evaluated the suitability of free energy perturbation (FEP) calculations as a tool for predicting the binding affinity of reversible covalent inhibitors of hCatL. Our strategy relies on the relative free energy calculated for both covalent and noncovalent complexes and the free energy changes have been compared with experimental data for eight nitrile-based inhibitors, including three new inhibitors of hCatL. Our results demonstrate that the covalent complex can be employed to properly rank the inhibitors. Nevertheless, a comparison of the free energy changes in both noncovalent and covalent states is valuable to interpret the effect triggered by the formation of the covalent bond on the interactions played by functional groups distant from the warhead. Overall, FEP can be employed as a powerful predictor tool in developing and understanding the activity of reversible covalent inhibitors.

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Section: Results and Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Predicting the Relative Binding Affinity for Reversible Covalent Inhibitors by Free Energy Perturbation Calculations

Bonatto

Shamim

Rocho

et al. 2021

J. Chem. Inf. Model.

Self Cite

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“…In general, the most effective inhibitors of cysteine proteases are peptide analogues bearing electrophilic warheads, which undergo reaction with the active-site cysteine ( Puzer et al, 2004 ; Cianni et al, 2019 ; and Cianni et al, 2021 ). The peptide or peptidomimetic moieties of such inhibitors are based on the substrate specificity of the target cysteine protease, and are therefore designed to selectively guide the appended warhead to the active-site of intent.…”

Section: Introductionmentioning

confidence: 99%

“…While peptidic aldehydes form reversible thiohemiacetal adducts with the active-site cysteines of cysteine proteases ( Cianni et al, 2021 ; Lewis and Wolfenden, 1977 ; Pehere et al, 2019 ; and Woo et al, 1995 ), and thereby afford exceptionally potent inhibition, free aldehydes are in general too reactive to provide therapeutic agents ( Kaplowitz, 2005 ; Gampe and Verma, 2020 ; and O'Brien et al, 2005 ). However, CAT811, a macrocyclic aldehyde which is an inhibitor of the cysteine protease calpain, may be applied topically to the eye leading to the reduction of cataract formation ( Morton et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Self-Masked Aldehyde Inhibitors of Human Cathepsin L Are Potent Anti-CoV-2 Agents

Zhu

Drelich

et al. 2022

Front. Chem.

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Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of compounds, self-masked aldehyde inhibitors (SMAIs) which are based on the dipeptide aldehyde inhibitor (Cbz-Phe-Phe-CHO, 1), for which the P1 Phe group contains a 1′-hydroxy group, effectively, an o-tyrosinyl aldehyde (Cbz-Phe-o-Tyr-CHO, 2; (Li et al. (2021) J. Med. Chem. 64, 11,267–11,287)). Compound 2 and other SMAIs exist in aqueous mixtures as stable δ-lactols, and apparent catalysis by the cysteine protease cruzain, the major cysteine protease of Trypanosoma cruzi, results in the opening of the lactol ring to afford the aldehydes which then form reversible thiohemiacetals with the enzyme. These SMAIs are also potent, time-dependent inhibitors of human cathepsin L (Ki = 11–60 nM), an enzyme which shares 36% amino acid identity with cruzain. As inactivators of cathepsin L have recently been shown to be potent anti-SARS-CoV-2 agents in infected mammalian cells (Mellott et al. (2021) ACS Chem. Biol. 16, 642–650), we evaluated SMAIs in VeroE6 and A549/ACE2 cells infected with SARS-CoV-2. These SMAIs demonstrated potent anti-SARS-CoV-2 activity with values of EC50 = 2–8 μM. We also synthesized pro-drug forms of the SMAIs in which the hydroxyl groups of the lactols were O-acylated. Such pro-drug SMAIs resulted in significantly enhanced anti-SARS-CoV-2 activity (EC50 = 0.3–0.6 μM), demonstrating that the O-acylated-SMAIs afforded a level of stability within infected cells, and are likely converted to SMAIs by the action of cellular esterases. Lastly, we prepared and characterized an SMAI in which the sidechain adjacent to the terminal aldehyde is a 2-pyridonyl-alanine group, a mimic of both phenylalanine and glutamine. This compound (9) inhibited both cathepsin L and 3CL protease at low nanomolar concentrations, and also exerted anti-CoV-2 activity in an infected human cell line.

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Some morpholine tethered novel aurones: Design, synthesis, biological, kinetic and molecular docking studies

Saroha,

Kumar,

Arya

et al. 2023

Bioorganic Chemistry

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Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Cited by 7 publications

References 52 publications

Predicting the Relative Binding Affinity for Reversible Covalent Inhibitors by Free Energy Perturbation Calculations

Predicting the Relative Binding Affinity for Reversible Covalent Inhibitors by Free Energy Perturbation Calculations

Self-Masked Aldehyde Inhibitors of Human Cathepsin L Are Potent Anti-CoV-2 Agents

Some morpholine tethered novel aurones: Design, synthesis, biological, kinetic and molecular docking studies

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