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1.
Front Chem ; 10: 867928, 2022.
Article in English | MEDLINE | ID: covidwho-2029956

ABSTRACT

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 (K i = 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.

2.
Frontiers in chemistry ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-1940350

ABSTRACT

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.

3.
Romanian Journal of Diabetes, Nutrition and Metabolic Diseases ; 29(1):22-27, 2022.
Article in English | EMBASE | ID: covidwho-1929129

ABSTRACT

Multisystem inflammatory syndrome (MIS) post-SARS-COV-2 infection has been described in children. Few case reports of MIS in adults are available, the majority described in young previously healthy persons. Here we report the case of MIS that meets the Center for Disease Control definition of MIS in adults in an elderly patient with known type 2 diabetes with a recent history of COVID-19. As the number of COVID-19 cases continues to rise, we believe that more and more cases of adult MIS will be reported. Thus, investigations aiming to characterize the full spectrum of clinical manifestations, to clarify the pathogenetic mechanisms leading to adult MIS as well as long-term consequences are needed.

4.
Diabetes Research and Clinical Practice ; 186, 2022.
Article in English | EMBASE | ID: covidwho-1894927

ABSTRACT

Background: Heart failure (HF) is a frequent comorbidity in type 2 diabetes (T2D) patients. Limited data on the prevalence of HF in T2D in Romanian clinical practice exist. Aim: This study addressed this knowledge gap by collecting recent information about HF prevalence in T2D. Method: FIND was a cross-sectional, observational study conducted in two large diabetes outpatient clinics from January to May 2020. Consecutive adult patients with T2D were enrolled upon expressing the written consent. Clinical data related to diabetes status was collected. The cardiology exam was performed as in clinical practice, after inclusion in the study. The cardiac assessment included natriuretic peptide testing, typical HF signs and symptoms, and echocardiography exam with left ventricle ejection fraction (LVEF) and structural abnormalities reported. Due to coronavirus disease-19 lockdown, the study was early terminated and some patients could not perform the cardiology exam. The per protocol population (PPP) included all T2D patients with cardiology exam conducted (270 out of 300 enrolled). Epidemiological methods have been used for the analysis of collected data with descriptive statistics. Results: The prevalence of HF was 30.7%. Most HF patients (83.1%) had preserved ejection fraction (LVEF ≥50%, HFpEF subgroup) and 16.9% mid-range ejection fraction (LVEF 40-49%, HFmrEF subgroup). The prevalence of HF typical symptoms was 57.0% in PPP group and 91.6% in HF subgroup. The echocardiography showed diastolic dysfunction (PPP: 87.3%, HF: 96.4%), cardiac structural changes (PPP: 64.8%, HF: 74.7%), and systolic dysfunction (PPP: 24.6%, HF: 41.0%). Natriuretic peptides were above the upper limit in 23.2% of PPP patients and 57.5% of the HF patients. The gender distribution was balanced (males: 50% in PPP, 50.6% in HF group). The mean age (SD) of patients was 63.8 (8.7), and 67.2 (7.8) years, with a mean duration of T2D (SD) of 11.1 (6.9), and 11.7 (7.0) years in PPP and HF groups, respectively. In the HF group, only 8.5% had a previous diagnosis of HF. In total, 98.2% of patients in PPP group received anti-diabetes treatment: metformin monotherapy (46.7%), oral anti-diabetes drugs combination (OAD) (26.7%), injectable GLP-1 receptor agonist (GLP-1 RA) (7.4%), and insulin (44.1%). Mean (SD) HbA1c levels were 7.9% (1.6) and 7.8% (1.6) in the PPP and HF groups, respectively. The prevalence of HF by anti-diabetes treatment was 29.6% in metformin only group, 30.6% in OAD group, 20.0% in GLP-1 RA group and 33.6% in insulin group. The treatment for HF following cardiac assessment included beta-blockers (82.4%), diuretics (52.7%), angiotensin converting enzymes inhibitors (47.3%), statins (31.1%), and angiotensin receptor blockers (25.7%). Discussion: FIND is the first study assessing the prevalence of HF in T2D in Romania. Almost one third of patients of the T2D patients had HF diagnosed by a cardiologist and for one in ten patients this was flagged only by the standard cardiologic exam at the time of study. HF prevalence rate was not influenced by diabetes duration or current diabetes treatment. An early clinical assessment of cardiovascular risk followed by tailored treatment approach to ensure cardioprotection and prevent complications is needed. Funding: AstraZeneca Romania.

5.
Romanian Journal of Diabetes, Nutrition and Metabolic Diseases ; 28(4):337-342, 2021.
Article in English | EMBASE | ID: covidwho-1614637

ABSTRACT

Obesity is a multisystem chronic disease which has reached epidemic/pandemic proportions worldwide and poses serious medical and societal challenges. Very soon after the COVID-19 outbreak in March 2020, it became clear that obesity is one of the main risk factors for severe forms of SARS-CoV-2 infections and for mortality due to COVID. The collision of the two pandemics – obesity and COVID-19, created the opportunity to revisit the national, regional, and global plans to tackle obesity and was a powerful driver for various organizations to shed a stronger light on obesity problem. On the other hand, experts in the field of obesity raised the idea that in order to reduce the burden of adiposity-related comorbidities, there is a need for a better alignment between staging systems taking into account the presence and severity of comorbidities and weight loss treatment guidelines which still use body mass index (BMI) thresholds to recommend strategies choice. In line with these recommendations, we propose a new obesity staging system, the risk of obesity (RO) score, based on three criteria: anthropometric, the burden of diseases and cardiovascular risk. Its utility in clinical practice will be further tested.

6.
ACS Chem Biol ; 16(4): 642-650, 2021 04 16.
Article in English | MEDLINE | ID: covidwho-1387141

ABSTRACT

Host-cell cysteine proteases play an essential role in the processing of the viral spike protein of SARS coronaviruses. K777, an irreversible, covalent inactivator of cysteine proteases that has recently completed phase 1 clinical trials, reduced SARS-CoV-2 viral infectivity in several host cells: Vero E6 (EC50< 74 nM), HeLa/ACE2 (4 nM), Caco-2 (EC90 = 4.3 µM), and A549/ACE2 (<80 nM). Infectivity of Calu-3 cells depended on the cell line assayed. If Calu-3/2B4 was used, EC50 was 7 nM, but in the ATCC Calu-3 cell line without ACE2 enrichment, EC50 was >10 µM. There was no toxicity to any of the host cell lines at 10-100 µM K777 concentration. Kinetic analysis confirmed that K777 was a potent inhibitor of human cathepsin L, whereas no inhibition of the SARS-CoV-2 cysteine proteases (papain-like and 3CL-like protease) was observed. Treatment of Vero E6 cells with a propargyl derivative of K777 as an activity-based probe identified human cathepsin B and cathepsin L as the intracellular targets of this molecule in both infected and uninfected Vero E6 cells. However, cleavage of the SARS-CoV-2 spike protein was only carried out by cathepsin L. This cleavage was blocked by K777 and occurred in the S1 domain of the SARS-CoV-2 spike protein, a different site from that previously observed for the SARS-CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of cathepsin L-mediated viral spike protein processing.


Subject(s)
Antiviral Agents/pharmacology , Cysteine Proteinase Inhibitors/pharmacology , Phenylalanine/pharmacology , Piperazines/pharmacology , SARS-CoV-2/drug effects , Tosyl Compounds/pharmacology , Animals , Cathepsin L/antagonists & inhibitors , Cathepsin L/metabolism , Cell Line, Tumor , Chlorocebus aethiops , Humans , Microbial Sensitivity Tests , Protein Domains , Proteolysis , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Internalization/drug effects
7.
J Med Chem ; 64(15): 11267-11287, 2021 08 12.
Article in English | MEDLINE | ID: covidwho-1319012

ABSTRACT

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 self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease-Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki* = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.


Subject(s)
Aldehydes/chemistry , COVID-19/drug therapy , Chagas Disease/drug therapy , Cysteine Proteinase Inhibitors/therapeutic use , SARS-CoV-2/enzymology , Trypanosoma cruzi/enzymology , Aldehydes/metabolism , Aldehydes/pharmacology , Cathepsin L/antagonists & inhibitors , Cathepsin L/metabolism , Cysteine Endopeptidases/metabolism , Cysteine Proteases/metabolism , Cysteine Proteinase Inhibitors/chemistry , Drug Design , Humans , Kinetics , Models, Molecular , Molecular Structure , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/metabolism , SARS-CoV-2/drug effects , Structure-Activity Relationship , Trypanosoma cruzi/drug effects
8.
bioRxiv ; 2020 Oct 30.
Article in English | MEDLINE | ID: covidwho-915969

ABSTRACT

K777 is a di-peptide analog that contains an electrophilic vinyl-sulfone moiety and is a potent, covalent inactivator of cathepsins. Vero E6, HeLa/ACE2, Caco-2, A549/ACE2, and Calu-3, cells were exposed to SARS-CoV-2, and then treated with K777. K777 reduced viral infectivity with EC50 values of inhibition of viral infection of: 74 nM for Vero E6, <80 nM for A549/ACE2, and 4 nM for HeLa/ACE2 cells. In contrast, Calu-3 and Caco-2 cells had EC50 values in the low micromolar range. No toxicity of K777 was observed for any of the host cells at 10-100 µM inhibitor. K777 did not inhibit activity of the papain-like cysteine protease and 3CL cysteine protease, encoded by SARS-CoV-2 at concentrations of ≤ 100 µM. These results suggested that K777 exerts its potent anti-viral activity by inactivation of mammalian cysteine proteases which are essential to viral infectivity. Using a propargyl derivative of K777 as an activity-based probe, K777 selectively targeted cathepsin B and cathepsin L in Vero E6 cells. However only cathepsin L cleaved the SARS-CoV-2 spike protein and K777 blocked this proteolysis. The site of spike protein cleavage by cathepsin L was in the S1 domain of SARS-CoV-2 , differing from the cleavage site observed in the SARS CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of viral spike protein processing.

9.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.10.23.347534

ABSTRACT

K777 is a di-peptide analog that contains an electrophilic vinyl-sulfone moiety and is a potent, covalent inactivator of cathepsins. Vero E6, HeLa/ACE2, Caco-2, A549/ACE2, and Calu-3, cells were exposed to SARS-CoV-2, and then treated with K777. K777 reduced viral infectivity with EC50 values of inhibition of viral infection of: 74 nM for Vero E6, <80 nM for A549/ACE2, and 4 nM for HeLa/ACE2 cells. In contrast, Calu-3 and Caco-2 cells had EC50 values in the low micromolar range. No toxicity of K777 was observed for any of the host cells at 10-100 M inhibitor. K777 did not inhibit activity of the papain-like cysteine protease and 3CL cysteine protease, encoded by SARS-CoV-2 at concentrations of [≤] 100 M. These results suggested that K777 exerts its potent anti-viral activity by inactivation of mammalian cysteine proteases which are essential to viral infectivity. Using a propargyl derivative of K777 as an activity-based probe, K777 selectively targeted cathepsin B and cathepsin L in Vero E6 cells. However only cathepsin L cleaved the SARS-CoV-2 spike protein and K777 blocked this proteolysis. The site of spike protein cleavage by cathepsin L was in the S1 domain of SARS-CoV-2 , differing from the cleavage site observed in the SARS CoV-1 spike protein. These data support the hypothesis that the antiviral activity of K777 is mediated through inhibition of the activity of host cathepsin L and subsequent loss of viral spike protein processing.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , COVID-19
10.
Cureus ; 12(8): e10154, 2020 Aug 31.
Article in English | MEDLINE | ID: covidwho-745291

ABSTRACT

Moraxella osleonsis  (M.osleonsis ) is an organism that rarely presents with bacteremia in immunocompetent patients. We report a case of an immunocompetent 59-year-old male with a recent SARS-CoV-2 infection that developed M. osleonsis bacteremia. We believe that SARS-CoV-2 infection may have played a role in developing M. osleonsis  bacteremia in this patient and may be one of the first reported cases of such bacteremia in a COVID-19 patient.

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