Viral protease inhibitors affect the production of virulence factors in Cryptococcus neoformans

2012 ◽  
Vol 58 (7) ◽  
pp. 932-936 ◽  
Author(s):  
J.J.C. Sidrim ◽  
L.V. Perdigão-Neto ◽  
R.A. Cordeiro ◽  
R.S.N. Brilhante ◽  
J.J.G. Leite ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Protease Inhibitors ◽  
Virulence Factors ◽  
Fungal Growth ◽  
Antiretroviral Drugs ◽  
Specific Pattern ◽  
Phospholipase Activity ◽  
Viral Protease ◽  
Capsule Production ◽  
Capsule Thickness

The effects of the protease inhibitors saquinavir, darunavir, ritonavir, and indinavir on growth inhibition, protease and phospholipase activities, as well as capsule thickness of Cryptococcus neoformans were investigated. Viral protease inhibitors did not reduce fungal growth when tested in concentrations ranging from 0.001 to 1.000 mg/L. A tendency toward increasing phospholipase activity was observed with the highest tested drug concentration in a strain-specific pattern. However, these drugs reduced protease activity as well as capsule production. Our results confirm a previous finding that antiretroviral drugs affect the production of important virulence factors of C. neoformans.

Pharmacokinetics, Placental and Breast Milk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV

2019 ◽  
Vol 25 (5) ◽  
pp. 556-576 ◽  
Author(s):  
E.M. Hodel ◽  
C. Marzolini ◽  
C. Waitt ◽  
N. Rakhmanina
Keyword(s):  
Breast Milk ◽  
Protease Inhibitors ◽  
Drug Class ◽  
Drug Transporters ◽  
Maternal Plasma ◽  
Antiretroviral Drugs ◽  
Physiological Changes ◽  
Women Living With Hiv ◽  
Living With Hiv ◽  
In Pregnancy

Background:Remarkable progress has been achieved in the identification of HIV infection in pregnant women and in the prevention of vertical HIV transmission through maternal antiretroviral treatment (ART) and neonatal antiretroviral drug (ARV) prophylaxis in the last two decades. Millions of women globally are receiving combination ART throughout pregnancy and breastfeeding, periods associated with significant biological and physiological changes affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of ARVs. The objective of this review was to summarize currently available knowledge on the PK of ARVs during pregnancy and transport of maternal ARVs through the placenta and into the breast milk. We also summarized main safety considerations for in utero and breast milk ARVs exposures in infants.Methods:We conducted a review of the pharmacological profiles of ARVs in pregnancy and during breastfeeding obtained from published clinical studies. Selected maternal PK studies used a relatively rich sampling approach at each ante- and postnatal sampling time point. For placental and breast milk transport of ARVs, we selected the studies that provided ratios of maternal to the cord (M:C) plasma and breast milk to maternal plasma (M:P) concentrations, respectively.Results:We provide an overview of the physiological changes during pregnancy and their effect on the PK parameters of ARVs by drug class in pregnancy, which were gathered from 45 published studies. The PK changes during pregnancy affect the dosing of several protease inhibitors during pregnancy and limit the use of several ARVs, including three single tablet regimens with integrase inhibitors or protease inhibitors co-formulated with cobicistat due to suboptimal exposures. We further analysed the currently available data on the mechanism of the transport of ARVs from maternal plasma across the placenta and into the breast milk and summarized the effect of pregnancy on placental and of breastfeeding on mammal gland drug transporters, as well as physicochemical properties, C:M and M:P ratios of individual ARVs by drug class. Finally, we discussed the major safety issues of fetal and infant exposure to maternal ARVs.Conclusions:Available pharmacological data provide evidence that physiological changes during pregnancy affect maternal, and consequently, fetal ARV exposure. Limited available data suggest that the expression of drug transporters may vary throughout pregnancy and breastfeeding thereby possibly impacting the amount of ARV crossing the placenta and secreted into the breast milk. The drug transporter’s role in the fetal/child exposure to maternal ARVs needs to be better understood. Our analysis underscores the need for more pharmacological studies with innovative study design, sparse PK sampling, improved study data reporting and PK modelling in pregnant and breastfeeding women living with HIV to optimize their treatment choices and maternal and child health outcomes.

scholarly journals Protease Inhibitors as Antiviral Agents

1998 ◽  
Vol 11 (4) ◽  
pp. 614-627 ◽  
Author(s):  
A. K. Patick ◽  
K. E. Potts
Keyword(s):  
Protease Inhibitors ◽  
Viral Infections ◽  
Critical Role ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Structural Proteins ◽  
Viral Protease ◽  
Virus Particles ◽  
Viral Proteases ◽  
Viral Polyprotein

SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

scholarly journals Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro

2020 ◽  
Author(s):  
Leike Zhang ◽  
Jia Liu ◽  
Ruiyuan Cao ◽  
Mingyue Xu ◽  
Yan Wu ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
The Novel ◽  
Viral Protease ◽  
Antiviral Efficacy

scholarly journals Cell Wall-Associated Virulence Factors Contribute to Increased Resilience of Old Cryptococcus neoformans Cells

2019 ◽  
Vol 10 ◽  
Author(s):  
Erika P. Orner ◽  
Somanon Bhattacharya ◽  
Klea Kalenja ◽  
Danielle Hayden ◽  
Maurizio Del Poeta ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Virulence Factors

scholarly journals Peroxisomal and Mitochondrial β-Oxidation Pathways Influence the Virulence of the Pathogenic Fungus Cryptococcus neoformans

2012 ◽  
Vol 11 (8) ◽  
pp. 1042-1054 ◽  
Author(s):  
Matthias Kretschmer ◽  
Joyce Wang ◽  
James W. Kronstad
Keyword(s):  
Carbon Source ◽  
Cryptococcus Neoformans ◽  
Virulence Factor ◽  
Fungal Pathogens ◽  
Pathogenic Fungus ◽  
Subsequent Work ◽  
Content Type ◽  
Capsule Production ◽  
Human Pathogenic Fungus ◽  
Host Tissues

ABSTRACTAn understanding of the connections between metabolism and elaboration of virulence factors during host colonization by the human-pathogenic fungusCryptococcus neoformansis important for developing antifungal therapies. Lipids are abundant in host tissues, and fungal pathogens in the phylum basidiomycota possess both peroxisomal and mitochondrial β-oxidation pathways to utilize this potential carbon source. In addition, lipids are important signaling molecules in both fungi and mammals. In this report, we demonstrate that defects in the peroxisomal and mitochondrial β-oxidation pathways influence the growth ofC. neoformanson fatty acids as well as the virulence of the fungus in a mouse inhalation model of cryptococcosis. Disease attenuation may be due to the cumulative influence of altered carbon source acquisition or processing, interference with secretion, changes in cell wall integrity, and an observed defect in capsule production for the peroxisomal mutant. Altered capsule elaboration in the context of a β-oxidation defect was unexpected but is particularly important because this trait is a major virulence factor forC. neoformans. Additionally, analysis of mutants in the peroxisomal pathway revealed a growth-promoting activity forC. neoformans, and subsequent work identified oleic acid and biotin as candidates for such factors. Overall, this study reveals that β-oxidation influences virulence inC. neoformansby multiple mechanisms that likely include contributions to carbon source acquisition and virulence factor elaboration.

Deletion of the CAP10 gene of Cryptococcus neoformans results in a pleiotropic phenotype with changes in expression of virulence factors

2014 ◽  
Vol 165 (6) ◽  
pp. 399-410 ◽  
Author(s):  
Boris Tefsen ◽  
Jan Grijpstra ◽  
Soledad Ordonez ◽  
Menno Lammers ◽  
Irma van Die ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Virulence Factors ◽  
Pleiotropic Phenotype

scholarly journals Virulence Factors Contributing to Pathogenicity ofCandida tropicalisand Its Antifungal Susceptibility Profile

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Sachin C. Deorukhkar ◽  
Santosh Saini ◽  
Stephen Mathew
Keyword(s):  
Virulence Factors ◽  
Biofilm Formation ◽  
Antifungal Susceptibility ◽  
Common Species ◽  
Blood Cultures ◽  
Haemolytic Activity ◽  
Phospholipase Activity ◽  
Fluconazole Resistance ◽  
Activity Maximum ◽  
The Past

The incidence of invasive candidiasis has increased over the past few decades. AlthoughCandida albicansremains by far the most common species encountered, in recent years shift towards non-albicans Candidaspecies likeCandida tropicalisis noted. Here in this study we determined the virulence factors and antifungal susceptibility profile of 125C. tropicalisisolated from various clinical specimens. Biofilm formation was seen in 53 (42.4%) isolates. Coagulase production was noted in 18 (14.4%) isolates. Phospholipase enzyme was the major virulent factor produced byC. tropicalisisolates. A total of 39 biofilm forming isolates showed phospholipase activity. Proteinase activity was demonstrated by 65 (52%) isolates. A total of 38 (30.4%) isolates showed haemolytic activity. Maximum isolates demonstrated resistance to fluconazole. Fluconazole resistance was more common inC. tropicalisisolated from blood cultures. Antifungal resistance was more in isolates possessing the ability to produce phospholipase and biofilm.C. tropicalisexhibit a great degree of variation not only in their pathogenicity but also in their antifungal susceptibility profile. The identification of virulence attributes specific for each species and their correlation with each other will aid in the understanding of the pathogenesis of infection.

Investigation of Acid Proteinase and Phospholipase Activity as Virulence Factors in Clinical Aspergillus spp. Isolates

2014 ◽  
Vol 48 (3) ◽  
pp. 491-494 ◽  
Author(s):  
Asuman BİRİNCİ ◽  
Kemal BİLGİN ◽  
Yeliz TANRIVERDİ ÇAYCI
Keyword(s):  
Virulence Factors ◽  
Acid Proteinase ◽  
Phospholipase Activity
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