scholarly journals Main protease mutants of SARS-CoV-2 variants remain susceptible to PF-07321332

2021 ◽  
Author(s):  
Sven Ullrich ◽  
Kasuni B Ekanayake ◽  
Gottfried Otting ◽  
Christoph Nitsche
Keyword(s):  
Public Health ◽  
Clinical Relevance ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Spike Protein ◽  
Main Protease ◽  
Public Health Threat ◽  
Vitro Data ◽  
In Vitro Data

The COVID-19 pandemic continues to be a public health threat. Multiple mutations in the spike protein of emerging variants of SARS-CoV-2 appear to impact on the effectiveness of available vaccines. Specific antiviral agents are keenly anticipated but their efficacy may also be compromised in emerging variants. One of the most attractive coronaviral drug targets is the main protease (Mpro). A promising Mpro inhibitor of clinical relevance is the peptidomimetic PF-07321332. We expressed Mpro of five SARS-CoV-2 lineages (C.37 Lambda, B.1.1.318, B.1.2, B.1.351 Beta, P.2 Zeta), each of which carries a strongly prevalent missense mutation (G15S, T21I, L89F, K90R, L205V). Enzyme kinetics showed that these Mpro variants are similarly catalytically competent as the wildtype. We show that PF-07321332 has similar potency against the variants as against the wildtype. Our in vitro data suggest that the efficacy of specific Mpro inhibitors such as PF-07321332 is not compromised in current COVID-19 variants.

scholarly journals Substrate mapping and inhibitor profiling of falcipain-2, falcipain-3 and berghepain-2: implications for peptidase anti-malarial drug discovery

2006 ◽  
Vol 399 (1) ◽  
pp. 47-57 ◽  
Author(s):  
Manoj K. Ramjee ◽  
Nicholas S. Flinn ◽  
Tracy P. Pemberton ◽  
Martin Quibell ◽  
Yikang Wang ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Specific Substrate ◽  
Rational Drug ◽  
Parasite Plasmodium ◽  
Recognition Motifs ◽  
Synergistic Combinations ◽  
Vitro Data ◽  
In Vitro Data

The Plasmodium falciparum cysteine peptidases FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases and are therefore potential anti-malarial drug targets. To facilitate a rational drug discovery programme, in the current study we analysed the synthetic substrate and model inhibitor profiles of FP-2 and FP-3 as well as BP-2 (berghepain-2), an orthologue from the rodent parasite Plasmodium berghei. With respect to substrate catalysis, FP-2 exhibited a promiscuous substrate profile based around a consensus non-primeside motif, FP-3 was somewhat more restricted and BP-2 was comparatively specific. Substrate turnover for FP-2 was driven by a basic or acidic P1 residue, whereas for FP-3 turnover occurred predominately through a basic P1 residue only, and for BP-2, turnover was again mainly through a basic P1 residue for some motifs and surprisingly a glycine in the P1 position for other motifs. Within these P1 binding elements, additional recognition motifs were observed with subtle nuances that switched substrate turnover on or off through specific synergistic combinations. The peptidases were also profiled against reversible and irreversible cysteine peptidase inhibitors. The results re-iterated the contrasting kinetic behaviour of each peptidase as observed through the substrate screens. The results showed that the substrate and inhibitor preferences of BP-2 were markedly different from those of FP-2 and FP-3. When FP-2 and FP-3 were compared to each other they also displayed similarities and some significant differences. In conclusion, the in vitro data highlights the current difficulties faced by a peptidase directed anti-malarial medicinal chemistry programme where compounds need to be identified with potent activity against at least three peptidases, each of which displays distinct biochemical traits.

scholarly journals Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities

2021 ◽  
Author(s):  
Bruno Villoutreix ◽  
Rajagopal Krishnamoorthy ◽  
Ryad Tamouza ◽  
Marion Leboyer ◽  
Philippe Beaune
Keyword(s):  
High Throughput Screening ◽  
Psychiatric Patients ◽  
Antiviral Agents ◽  
Clinical Observations ◽  
Prophylactic Drugs ◽  
Initial Hypothesis ◽  
Antihistaminic Drugs ◽  
Vitro Data ◽  
In Vitro Data

<div> <div> <div><b>Introduction:</b> There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. <p><b>Objective:</b> We proposed, before summer 2020, that cationic amphiphilic psychotropic and antihistaminic drugs could protect psychiatric patients from SARS-CoV-2 infection based upon clinical observations. At that time, experimental in vitro data on SARS-CoV-2 were missing.</p> <p><b>Methods:</b> Open high-throughput screening results are now available at the NCATS COVID-19 portal and it is possible to investigate again our initial hypothesis using simple chemoinformatics approaches but this time with in vitro data on SARS-CoV-2.</p> <p><b>Results and Discussion:</b> We here revisit our initial hypothesis in the light of SARS-CoV-2 experimental screening results and propose that several cationic amphiphilic psychotropic and antihistaminic drugs could protect people from SARS-CoV-2 infection; some of these molecules have very limited adverse effects and could eventually be used as prophylactic drugs. Further, recent analyses of electronic health records reported by several research groups, including drug combinations, indicate that a small list of molecules could be of interest at different stages of the disease progression. Taken together, these observations suggest that clinical trials are now needed to fully evaluate the potentials of these potential small molecules broad-spectrum antiviral agents. Orally available drugs would indeed be of outmost importance to deal with COVID-19.</p> </div> </div> </div>

scholarly journals Chemoinformatic Analysis of Psychotropic and Antihistaminic Drugs in the Light of Experimental Anti-SARS-CoV-2 Activities

2021 ◽  
Author(s):  
Bruno Villoutreix ◽  
Rajagopal Krishnamoorthy ◽  
Ryad Tamouza ◽  
Marion Leboyer ◽  
Philippe Beaune
Keyword(s):  
High Throughput Screening ◽  
Psychiatric Patients ◽  
Antiviral Agents ◽  
Clinical Observations ◽  
Prophylactic Drugs ◽  
Initial Hypothesis ◽  
Antihistaminic Drugs ◽  
Vitro Data ◽  
In Vitro Data

<div> <div> <div><b>Introduction:</b> There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. <p><b>Objective:</b> We proposed, before summer 2020, that cationic amphiphilic psychotropic and antihistaminic drugs could protect psychiatric patients from SARS-CoV-2 infection based upon clinical observations. At that time, experimental in vitro data on SARS-CoV-2 were missing.</p> <p><b>Methods:</b> Open high-throughput screening results are now available at the NCATS COVID-19 portal and it is possible to investigate again our initial hypothesis using simple chemoinformatics approaches but this time with in vitro data on SARS-CoV-2.</p> <p><b>Results and Discussion:</b> We here revisit our initial hypothesis in the light of SARS-CoV-2 experimental screening results and propose that several cationic amphiphilic psychotropic and antihistaminic drugs could protect people from SARS-CoV-2 infection; some of these molecules have very limited adverse effects and could eventually be used as prophylactic drugs. Further, recent analyses of electronic health records reported by several research groups, including drug combinations, indicate that a small list of molecules could be of interest at different stages of the disease progression. Taken together, these observations suggest that clinical trials are now needed to fully evaluate the potentials of these potential small molecules broad-spectrum antiviral agents. Orally available drugs would indeed be of outmost importance to deal with COVID-19.</p> </div> </div> </div>

Use of Toxicokinetics in Risk Assessment Based on In Vitro Data

1993 ◽  
Vol 21 (2) ◽  
pp. 173-180
Author(s):  
Gunnar Johanson
Keyword(s):  
Risk Assessment ◽  
Whole Body ◽  
External Exposure ◽  
Target Dose ◽  
Toxic Response ◽  
Route Of Exposure ◽  
Vitro Data ◽  
In Vitro Data

This presentation addresses some aspects of the methodology, advantages and problems associated with toxicokinetic modelling based on in vitro data. By using toxicokinetic models, particularly physiologically-based ones, it is possible, in principle, to describe whole body toxicokinetics, target doses and toxic effects from in vitro data. Modelling can be divided into three major steps: 1) to relate external exposure (applied dose) of xenobiotic to target dose; 2) to establish the relationship between target dose and effect (in vitro data, e.g. metabolism in microsomes, partitioning in tissue homogenates, and toxicity in cell cultures, are useful in both steps); and 3) to relate external exposure to toxic effect by combining the first two steps. Extrapolations from in vitro to in vivo, between animal and man, and between high and low doses, can easily be carried out by toxicokinetic simulations. In addition, several factors that may affect the toxic response by changing the target dose, such as route of exposure and physical activity, can be studied. New insights concerning the processes involved in toxicity often emerge during the design, refinement and validation of the model. The modelling approach is illustrated by two examples: 1) the carcinogenicity of 1,3-butadiene; and 2) the haematotoxicity of 2-butoxyethanol. Toxicokinetic modelling is an important tool in toxicological risk assessment based on in vitro data. Many factors, some of which can, and should be, studied in vitro, are involved in the expression of toxicity. Successful modelling depends on the identification and quantification of these factors.

scholarly journals Lymphocutaneous spread of Mycobacterium elephantis in an immunocompetent individual: A case report

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110349
Author(s):  
Brett D Edwards ◽  
Ranjani Somayaji ◽  
Dina Fisher ◽  
Justin C Chia
Keyword(s):  
Case Report ◽  
Chronic Lung Disease ◽  
Contaminated Soil ◽  
Lung Abscess ◽  
Immunocompetent Individual ◽  
First Case ◽  
Antimycobacterial Agents ◽  
Vitro Data ◽  
In Vitro Data

Mycobacterium elephantis was first described when isolated from an elephant that succumbed to lung abscess. However, despite this namesake, it is not associated with animals and has been described most often as a probable colonizer rather than pathogen in humans with chronic lung disease. In this report, we describe the first case of lymphocutaneous infection from M. elephantis, likely as a result of cutaneous inoculation with contaminated soil. This offers further evidence to its capabilities as a pathogen. We provide a review of the limited prior reports of M. elephantis and outline the available in vitro data on efficacy of various antimycobacterial agents.

Prediction of CYP2D6 Drug Interactions from In Vitro Data: Evidence for Substrate-Dependent Inhibition

2011 ◽  
Vol 40 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Brooke M. VandenBrink ◽  
Robert S. Foti ◽  
Dan A. Rock ◽  
Larry C. Wienkers ◽  
Jan L. Wahlstrom
Keyword(s):  
Drug Interactions ◽  
Dependent Inhibition ◽  
Vitro Data ◽  
In Vitro Data

Pharmacokinetics and Pharmacodynamics of Antistaphylococcal Antibiotics in Continuous Ambulatory Peritoneal Dialysis Patients

1993 ◽  
Vol 13 (2_suppl) ◽  
pp. 367-371 ◽  
Author(s):  
Erich Keller
Keyword(s):  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Inhibitory Concentration ◽  
Pharmacokinetic Data ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Antistaphylococcal Activity ◽  
Cure Rates ◽  
Vitro Data ◽  
In Vitro Data

Staphylococci are the leading pathogens In continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Vancomycin appears to be an outstanding antistaphylococcal drug because resistance to It Is nearly absent. The pharmacokinetics of vancomycin and clinical cure rates of peritonitis with different dosing guidelines have been studied extensively. Different dosing guidelines with IP or IV loading doses followed or not followed by IP maintenance doses are used successfully, despite the fact that some of the dosing schemes produce apparently suboptimal drug levels referring to In vitro data like the MIC value (minimum Inhibitory concentration). Alternatively, amlnoglycosldes, cephalosporlns, Isoxazolyl penicillins, and broad-spectrum penicillins combined with betalactamase Inhibitors may be used for the treatment of gram-positive peritonitis. For the above panicillins pharmacokinetic data are scarce, and clinical experience is limited. Rifampin has excellent Intracellular antistaphylococcal activity and should be used In combination with other antibiotics. Although pharmacokinetic data are lacking, rifampin dosages do not require adaptation to renal function or replacement therapy.

scholarly journals Kenyan Plasmodium falciparum Field Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

1998 ◽  
Vol 42 (1) ◽  
pp. 164-169 ◽  
Author(s):  
A. Nzila-Mounda ◽  
E. K. Mberu ◽  
C. H. Sibley ◽  
C. V. Plowe ◽  
P. A. Winstanley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
Drug Response ◽  
Point Mutations ◽  
Distinct Group ◽  
Wild Type ◽  
Field Isolates ◽  
Vitro Data ◽  
In Vitro Data

ABSTRACT Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P< 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

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