Synthesis and evaluation of potent human immunodeficiency virus 1 protease inhibitors with epimeric isopropanol as novel P1′ ligands

2020 ◽  
Vol 12 (9) ◽  
pp. 775-794 ◽  
Author(s):  
Mei Zhu ◽  
Ling Ma ◽  
Biao Dong ◽  
Guoning Zhang ◽  
Juxian Wang ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Design Strategy ◽  
Drug Resistant ◽  
Inhibition Activity ◽  
Protease Enzyme ◽  
Immunodeficiency Virus ◽  
Resistant Strains ◽  
Backbone Atoms ◽  
Drug Resistant Strains ◽  
Hiv 1

Aim: HIV-1 protease inhibitors regimens suffered from a number of drawbacks, among which, the most egregious issue was the growing emergence of drug-resistant strains. Materials & methods: The design strategy of maximizing the protease active site interactions with the inhibitor, especially promoting extensive hydrogen bonding with the protein backbone atoms, might be in favor of combating drug resistance. A series of HIV-1 protease inhibitors that incorporated enantiomeric isopropanols as the P1′ ligands in combination with phenols as the P2 ligands were reported herein. Results: A number of inhibitors displayed potent protease enzyme inhibition activity. In particular, inhibitor 14c showed comparable potency as darunavir with IC50 value of 1.91 nM and activity against darunavir-resistant HIV-1 variants. Conclusion: The new kind of HIV-1 protease inhibitors deserves further study.

scholarly journals Clinical Significance and Characterization of AZT-Resistant Strains of HIV-1

1991 ◽  
Vol 2 (1) ◽  
pp. 5-11 ◽  
Author(s):  
Mark A Wainberg ◽  
Ronald Rooke ◽  
Michel Tremblay ◽  
XuGuang Li ◽  
Michael A Parniak ◽  
...  
Keyword(s):  
Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Resistant Strains ◽  
Drug Resistant Phenotype ◽  
Asymptomatic Subjects ◽  
Drug Resistant Strains ◽  
Hiv 1

A number of laboratories have now independently confirmed that zidovudine (AZT)-resistant strains of human immunodeficiency virus type 1 (HIV-1) may be isolated from patients undergoing prolonged therapy with this drug. In certain instances, such drug-resistant viral isolates have been obtained from patients with clinical acquired immune deficiency syndrome (AIDS), while in others, isolation of drug-resistant strains has been achieved in the case of HIV seropositive, asymptomatic subjects. Most of the evidence points to a series of mutations within the polymerase gene of HIV-1, which encodes viral reverse transcriptase, as being responsible for development of the drug-resistant phenotype. It further appears that over 50% of patients treated with AZT for periods longer than six months are likely to yield drug-resistant strains of HIV-1 in their circulation. Furthermore, the development of drug resistance soon after initiation of AZT therapy may potentially be correlated with the likelihood of AZT treatment failure. In several instances, cross resistance has been observed between AZT and other nucleosides being considered for potential therapy of HIV-1-associated disease.

Rates of transmission of antiretroviral drug resistant strains of HIV-1

2003 ◽  
Vol 26 (2) ◽  
pp. 153-161 ◽  
Author(s):  
Palanee Ammaranond ◽  
Philip Cunningham ◽  
Robert Oelrichs ◽  
Kazuo Suzuki ◽  
Claire Harris ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Antiretroviral Drug ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Hiv 1

scholarly journals R88-APOBEC3Gm Inhibits the Replication of Both Drug-resistant Strains of HIV-1 and Viruses Produced From Latently Infected Cells

2014 ◽  
Vol 3 ◽  
pp. e151 ◽  
Author(s):  
Xiaoxia Wang ◽  
Zhujun Ao ◽  
Kallesh Danappa Jayappa ◽  
Bei Shi ◽  
Gary Kobinger ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Latently Infected ◽  
Infected Cells ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Hiv 1

Low rate of genotypic HIV-1 drug-resistant strains in the Senegalese government initiative of access to antiretroviral therapy

AIDS ◽  
2003 ◽  
Vol 17 ◽  
pp. S31-S38 ◽  
Author(s):  
Laurence Vergne ◽  
Coumba Touré Kane ◽  
Christian Laurent ◽  
Ndella Diakhaté ◽  
Ndeye Fatou Ngom Gueye ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Drug Resistant ◽  
Resistant Strains ◽  
Government Initiative ◽  
Drug Resistant Strains ◽  
Hiv 1 ◽  
Low Rate

Evaluation of 4-thiazolidinone derivatives as potential reverse transcriptase inhibitors against HIV-1 drug resistant strains

2017 ◽  
Vol 71 ◽  
pp. 211-218 ◽  
Author(s):  
Rahul Suryawanshi ◽  
Sushama Jadhav ◽  
Nandini Makwana ◽  
Dipen Desai ◽  
Devidas Chaturbhuj ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Drug Resistant ◽  
Reverse Transcriptase Inhibitors ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Hiv 1

scholarly journals Cellular HIV-1 DNA Levels in Drug Sensitive Strains Are Equivalent to Those in Drug Resistant Strains in Newly-Diagnosed Patients in Europe

PLoS ONE ◽  
2010 ◽  
Vol 5 (6) ◽  
pp. e10976 ◽  
Author(s):  
Victoria L. Demetriou ◽  
David A. M. C. van de Vijver ◽  
Ioanna Kousiappa ◽  
Claudia Balotta ◽  
Bonaventura Clotet ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Newly Diagnosed ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Hiv 1

scholarly journals Novel HIV-1 Protease Inhibitors (PIs) Containing a Bicyclic P2 Functional Moiety, Tetrahydropyrano-Tetrahydrofuran, That Are Potent against Multi-PI-Resistant HIV-1 Variants

2011 ◽  
Vol 55 (4) ◽  
pp. 1717-1727 ◽  
Author(s):  
Kazuhiko Ide ◽  
Manabu Aoki ◽  
Masayuki Amano ◽  
Yasuhiro Koh ◽  
Ravikiran S. Yedidi ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Protease Inhibitors ◽  
Main Chain ◽  
Hydrophobic Interactions ◽  
Drug Resistant ◽  
Hydrogen Bonding Interactions ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACTWe identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% effective concentration (EC50s) of 2.6 to 32.6 nM. GRL-1398 was significantly more potent against such variants than DRV with EC50s of 0.1 to 5.7 nM. GRL-1388 and -1398 were also potent against multiple-PI-resistant clinical HIV-1 variants (CLHIV-1MDR) with EC50s ranging from 2.7 to 21.3 nM and from 0.3 to 4.8 nM, respectively. A highly DRV-resistant HIV-1 variant selectedin vitroremained susceptible to GRL-1398 with the EC50of 21.9 nM, while the EC50of DRV was 214.1 nM. When HIV-1NL4-3was selected with GRL-1398, four amino acid substitutions—leucine to phenylalanine at a position 10 (L10F), A28S, L33F, and M46I—emerged, ultimately enabling the virus to replicate in the presence of >1.0 μM the compound beyond 57 weeks of selection. When a mixture of 10 differentCLHIV-1MDRstrains was selected, the emergence of resistant variants was more substantially delayed with GRL-1398 than with GRL-1388 and DRV. Modeling analyses revealed that GRL-1398 had greater overall hydrogen bonding and hydrophobic interactions than GRL-1388 and DRV and that GRL-1388 and -1398 had hydrogen bonding interactions with the main chain of the active-site amino acids (Asp29 and Asp30) of protease. The present findings warrant that GRL-1398 be further developed as a potential drug for treating individuals with HIV-1 infection.

Sign in / Sign up

Export Citation Format

Share Document