Patent Evaluation: Cyclic ureas and analogues useful as retroviral protease inhibitors

1993 ◽  
Vol 3 (11) ◽  
pp. 1663-1664
Keyword(s):  
Protease Inhibitors ◽  
Patent Evaluation ◽  
Retroviral Protease

scholarly journals Anti-Retroviral Protease Inhibitors - ‘A Two Edged Sword?’

IUBMB Life ◽  
2008 ◽  
Vol 55 (2) ◽  
pp. 67-70 ◽  
Author(s):  
Ralph J. Germinario
Keyword(s):  
Protease Inhibitors ◽  
Retroviral Protease

Effects of Retroviral Protease Inhibitors on Proteasome Function and Processing of HIV-Derived MHC Class I-Restricted Cytotoxic T Lymphocyte Epitopes

2001 ◽  
Vol 17 (11) ◽  
pp. 1063-1066 ◽  
Author(s):  
Anthony D. Kelleher ◽  
Bruce L. Booth ◽  
Andrew K. Sewell ◽  
Annette Oxenius ◽  
Vincenzo Cerundolo ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Retroviral Protease

scholarly journals Deciphering the targets of retroviral protease inhibitors in Plasmodium berghei

2018 ◽  
Author(s):  
Noah Machuki ◽  
Reagan Mogire ◽  
Loise Ndung’u ◽  
Peter Mwitari ◽  
Francis Kimani ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Plasmodium Berghei ◽  
Parasite Growth ◽  
Blood Stage ◽  
Asexual Blood Stage ◽  
Parasite Fitness ◽  
Retroviral Protease ◽  
Stage Parasite ◽  
Aspartyl Proteases

AbstractRetroviral protease inhibitors (RPIs) such as lopinavir (LP) and saquinavir (SQ) are active against Plasmodium parasites. However, the exact molecular target(s) for these RPIs in the Plasmodium parasites remains poorly understood. We hypothesised that LP and SQ suppress parasite growth through inhibition of aspartyl proteases. Using reverse genetics approach, we embarked on separately generating knockout (KO) parasite lines lacking Plasmepsin 4 (PM4), PM7, PM8, or DNA damage-inducible protein 1 (Ddi1) in the rodent malaria parasite Plasmodium berghei ANKA. We then tested the suppressive profiles of the LP/Ritonavir (LP/RT) and SQ/RT as well as antimalarials; Amodiaquine (AQ) and Piperaquine (PQ) against the KO parasites in the standard 4-day suppressive test. The Ddi1 gene proved refractory to deletion suggesting that the gene is essential for the growth of the asexual blood stage parasites. Our results revealed that deletion of PM4 significantly reduces normal parasite growth rate phenotype (P = 0.003). Unlike PM4_KO parasites which were less susceptible to LP and SQ (P = 0.036, P = 0.030), the suppressive profiles for PM7_KO and PM8_KO parasites were comparable to those for the WT parasites. This finding suggests a potential role of PM4 in the LP and SQ action. On further analysis, modelling and molecular docking studies revealed that both LP and SQ displayed high binding affinities (-6.3 kcal/mol to -10.3 kcal/mol) towards the Plasmodium aspartyl proteases. We concluded that PM4 plays a vital role in assuring asexual stage parasite fitness and might be mediating LP and SQ action. The essential nature of the Ddi1 gene warrants further studies to evaluate its role in the parasite asexual blood stage growth as well as a possible target for the RPIs.Author summaryThe antiretroviral drugs (ARVs) such as LP or SQ that inhibit viral proteases reduce the rate of multiplication of the malaria parasites. The mode of action of these drugs against the parasites is however poorly understood. The proteases are among the enzymes that play essential roles in Plasmodium parasites. We sought to investigate the possible mode of action of these drugs by generating mutant parasites lacking specific aspartyl proteases namely PM4, PM7, PM8 or Ddi1 and then evaluate the susceptibility of the mutants to LP and SQ. We successfully generated parasites lacking either PM4, PM7 or PM8 but Ddi1 gene was refractory to deletion. From our data, we demonstrate that, unlike PM7 and PM8, the PM4 and Ddi1 are essential enzymes for asexual blood stage parasite fitness and survival and that the PM4 might be a target for the viral protease inhibitors in reducing parasite growth and multiplication. Further experiments using molecular docking tools show that LP or SQ have a high binding affinity for the Plasmodium aspartyl proteases.

Luminometric method for screening retroviral protease inhibitors

2005 ◽  
Vol 345 (1) ◽  
pp. 96-101 ◽  
Author(s):  
Dana Horáková ◽  
Michaela Rumlová ◽  
Iva Pichová ◽  
Tomáš Ruml
Keyword(s):  
Protease Inhibitors ◽  
Retroviral Protease

scholarly journals Deciphering the targets of retroviral protease inhibitors in Plasmodium berghei

PLoS ONE ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. e0201556 ◽  
Author(s):  
Noah Machuki Onchieku ◽  
Reagan Mogire ◽  
Loise Ndung'u ◽  
Peter Mwitari ◽  
Francis Kimani ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Plasmodium Berghei ◽  
Retroviral Protease

scholarly journals Dyslipidemia due to retroviral protease inhibitors

2002 ◽  
Vol 8 (4) ◽  
pp. 308-308 ◽  
Author(s):  
Anthony D. Kelleher ◽  
Andrew K. Sewell ◽  
David A. Price
Keyword(s):  
Protease Inhibitors ◽  
Retroviral Protease

scholarly journals Inhibition Profiling of Retroviral Protease Inhibitors Using an HIV-2 Modular System

Viruses ◽  
2015 ◽  
Vol 7 (12) ◽  
pp. 6152-6162 ◽  
Author(s):  
Mohamed Mahdi ◽  
Zsófia Szojka ◽  
János Mótyán ◽  
József Tőzsér
Keyword(s):  
Protease Inhibitors ◽  
Modular System ◽  
Retroviral Protease
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