Cyclic Urea Amides:  HIV-1 Protease Inhibitors with Low Nanomolar Potency against both Wild Type and Protease Inhibitor Resistant Mutants of HIV

1997 ◽  
Vol 40 (2) ◽  
pp. 181-191 ◽  
Author(s):  
Prabhakar K. Jadhav ◽  
Paul Ala ◽  
Francis J. Woerner ◽  
Chong-Hwan Chang ◽  
Sena S. Garber ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Wild Type ◽  
Resistant Mutants ◽  
Hiv 1

Discovery of Novel Urea-Based Hepatitis C Protease Inhibitors with High Potency against Protease-Inhibitor-Resistant Mutants

2012 ◽  
Vol 55 (7) ◽  
pp. 3021-3026 ◽  
Author(s):  
Wieslaw M. Kazmierski ◽  
Robert Hamatake ◽  
Maosheng Duan ◽  
Lois L. Wright ◽  
Gary K. Smith ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
High Potency ◽  
Resistant Mutants

scholarly journals Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Shin-ichiro Hattori ◽  
Hironori Hayashi ◽  
Haydar Bulut ◽  
Kalapala Venkateswara Rao ◽  
Prasanth R. Nyalapatla ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Active Site ◽  
Fluorine Atom ◽  
Halogen Bond ◽  
The Novel ◽  
Wild Type ◽  
Flap Region ◽  
Hiv 1

ABSTRACTWe generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2′-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2′ ligands, respectively. GRL-001-15 and GRL-003-15 havemeta-monofluorophenyl andpara-monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (EC50s) of 57 and 50 pM, respectively, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CC50s) of 38 and 11 μM, respectively. The activity of GRL-001-15 against multi-PI-resistant HIV-1 variants was generally greater than that of GRL-003-15. The EC50of GRL-001-15 against an HIV-1 variant that was highly resistant to multiple PIs, including darunavir (DRV) (HIV-1DRVRP30), was 0.17 nM, and that of GRL-003-15 was 3.3 nM, while DRV was much less active, with an EC50of 216 nM. The emergence of HIV-1 variants resistant to GRL-001-15 and GRL-003-15 was significantly delayed compared to that of variants resistant to selected PIs, including DRV. Structural analyses of wild-type protease (PRWT) complexed with the novel PIs revealed that GRL-001-15’smeta-fluorine atom forms halogen bond interactions (2.9 and 3.0 Å) with Gly49 and Ile50, respectively, of the protease flap region and with Pro81′ (2.7 and 3.2 Å), which is located close to the protease active site, and that two fluorine atoms of GRL-142-13 form multiple halogen bond interactions with Gly49, Ile50, Pro81′, Ile82′, and Arg8′. In contrast, GRL-003-15 forms halogen bond interactions with Pro81′ alone, suggesting that the reduced antiviral activity of GRL-003-15 is due to the loss of the interactions with the flap region.

scholarly journals Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease†

2007 ◽  
Vol 50 (18) ◽  
pp. 4509-4515 ◽  
Author(s):  
Yuan-Fang Wang ◽  
Yunfeng Tie ◽  
Peter I. Boross ◽  
Jozsef Tozser ◽  
Arun K. Ghosh ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Wild Type ◽  
Antiviral Compound ◽  
Structural Interactions ◽  
Resistant Mutants ◽  
Hiv 1

Pentacycloundecane derived hydroxy acid peptides: A new class of irreversible non-scissile ether bridged type isoster as potential HIV-1 wild type C-SA protease inhibitors

2012 ◽  
Vol 40 ◽  
pp. 19-29 ◽  
Author(s):  
Rajshekhar Karpoormath ◽  
Yasien Sayed ◽  
Patrick Govender ◽  
Thavendran Govender ◽  
Hendrik G. Kruger ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Hydroxy Acid ◽  
Wild Type ◽  
New Class ◽  
Type C ◽  
Hiv 1

scholarly journals Molecular Basis for Increased Susceptibility of Isolates with Atazanavir Resistance-Conferring Substitution I50L to Other Protease Inhibitors

2005 ◽  
Vol 49 (9) ◽  
pp. 3825-3832 ◽  
Author(s):  
Joseph Yanchunas ◽  
David R. Langley ◽  
Li Tao ◽  
Ronald E. Rose ◽  
Jacques Friborg ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Cross Resistance ◽  
Titration Calorimetry ◽  
Binding Affinities ◽  
The Novel ◽  
Immunodeficiency Virus ◽  
Effective Drugs ◽  
Hiv 1

ABSTRACT Protease inhibitors (PIs) are highly effective drugs against the human immunodeficiency virus (HIV), yet long-term therapeutic use is limited by emergence of HIV type 1 (HIV-1) protease substitutions that confer cross-resistance to multiple protease inhibitor drugs. Atazanavir is a highly potent HIV protease inhibitor with a distinct resistance profile that includes effectiveness against most HIV-1 isolates resistant to one or two PIs. The signature resistance substitution for atazanavir is I50L, and it is frequently (53%) accompanied by a compensatory A71V substitution that helps restore viability and increases atazanavir resistance levels. We measured the binding affinities of wild-type (WT) and I50L/A71V HIV-1 proteases to atazanavir and other currently approved PIs (ritonavir, lopinavir, saquinavir, nelfinavir, indinavir, and amprenavir) by isothermal titration calorimetry. Remarkably, we find that all of the PIs have 2- to 10-fold increased affinities for I50L/A71V protease, except for atazanavir. The results are also manifested by thermal stability measures of affinity for WT and I50L/A71V proteases. Additional biophysical and enzyme kinetics experiments show I50L/A71V protease is a stable enzyme with catalytic activity that is slightly reduced (34%) relative to the WT. Computational modeling reveals that the unique resistance phenotype of I50L/A71V protease likely originates from bulky tert-butyl groups at P2 and P2′ (specific to atazanavir) that sterically clash with methyl groups on residue L50. The results of this study provide a molecular understanding of the novel hypersusceptibility of atazanavir-resistant I50L/A71V-containing clinical isolates to other currently approved PIs.

scholarly journals In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors

2008 ◽  
Vol 52 (4) ◽  
pp. 1545-1548 ◽  
Author(s):  
Delphine Desbois ◽  
Bénédicte Roquebert ◽  
Gilles Peytavin ◽  
Florence Damond ◽  
Gilles Collin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Wild Type ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Phenotypic Susceptibility

ABSTRACT We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.

scholarly journals Interplay between Single Resistance-Associated Mutations in the HIV-1 Protease and Viral Infectivity, Protease Activity, and Inhibitor Sensitivity

2011 ◽  
Vol 56 (2) ◽  
pp. 623-633 ◽  
Author(s):  
Gavin J. Henderson ◽  
Sook-Kyung Lee ◽  
David M. Irlbeck ◽  
Janera Harris ◽  
Melissa Kline ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Protease Activity ◽  
Leukemia Virus ◽  
Fold Increase ◽  
Pleiotropic Effect ◽  
Viral Fitness ◽  
Resistance Mutations ◽  
Primary Resistance ◽  
Hiv 1

ABSTRACTResistance-associated mutations in the HIV-1 protease modify viral fitness through changes in the catalytic activity and altered binding affinity for substrates and inhibitors. In this report, we examine the effects of 31 mutations at 26 amino acid positions in protease to determine their impact on infectivity and protease inhibitor sensitivity. We found that primary resistance mutations individually decrease fitness and generally increase sensitivity to protease inhibitors, indicating that reduced virion-associated protease activity reduces virion infectivity and the reduced level of per virion protease activity is then more easily titrated by a protease inhibitor. Conversely, mutations at more variable positions (compensatory mutations) confer low-level decreases in sensitivity to all protease inhibitors with little effect on infectivity. We found significant differences in the observed effect on infectivity with a pseudotype virus assay that requires the protease to cleave the cytoplasmic tail of the amphotropic murine leukemia virus (MuLV) Env protein. Additionally, we were able to mimic the fitness loss associated with resistance mutations by directly reducing the level of virion-associated protease activity. Virions containing 50% of a D25A mutant protease were 3- to 5-fold more sensitive to protease inhibitors. This level of reduction in protease activity also resulted in a 2-fold increase in sensitivity to nonnucleoside inhibitors of reverse transcriptase and a similar increase in sensitivity to zidovudine (AZT), indicating a pleiotropic effect associated with reduced protease activity. These results highlight the interplay between enzyme activity, viral fitness, and inhibitor mechanism and sensitivity in the closed system of the viral replication complex.

scholarly journals An inhibitor-interaction intermediate of HIV-1 protease, revealed by Isothermal Titration Calorimetry and NMR spectroscopy

2018 ◽  
Author(s):  
Shahid N Khan ◽  
John D Persons ◽  
Michel Guerrero ◽  
Tatiana V. Ilina ◽  
Masayuki Oda ◽  
...  
Keyword(s):  
Heat Flow ◽  
Isothermal Titration Calorimetry ◽  
Titration Calorimetry ◽  
Drug Resistant ◽  
Wild Type ◽  
Binding Experiment ◽  
Direct Experiment ◽  
Resistant Mutants ◽  
Inhibitor Interaction ◽  
Hiv 1

AbstractSome of drug-resistant mutants of HIV-1 protease (PR), such as a clinically-relevant drug- resistant PR mutant (Flap+(I54V)) containing L10I, G48V, I54V and V82A mutations, produce significant changes in the balance between entropy and enthalpy of the drug-PR interactions, compared to the wild-type (WT) PR. Here, to gain a comprehensive understanding of the entropy-enthalpy compensation effects, we compared nuclear magnetic resonance (NMR), fluorescence spectroscopy and isothermal titration calorimetry (ITC) data of a WT PR with Flap+(I54V)and related mutants: (1) Flap+(I54V); (2) Flap+(I54A)which evolves from Flap+(I54V)in the continued presence of inhibitor yet does not exhibit entropy-enthalpy compensation; and (3) Flap+(I54), a control mutant that contains only L10I, G48V and V82A mutations. Our data indicate that WT and Flap+(I54A)show enthalpy-driven inhibitor-interaction, while Flap+(I54)and Flap+(I54V)exhibit entropy-driven inhibitor interaction. Interestingly, Flap+(I54A)exhibited significantly slower heat flow in the competitive ITC experiment with a strong binder, darunavir, and a weak binder, acetyl-pepstatin, but did not exhibit such slow heat flow in the direct inhibitor-titration experiments. NMR confirmed replacement of the weak binder by the strong binder in a competitive manner. This difference in the heat flow of the competitive binding experiment compared to the direct experiment can only be explained by assuming an inhibitor-bound intermediate pathway. A similar, but attenuated, tendency for slow heat flow was also detected in the competitive experiment with WT. Overall, our data suggests that an inhibitor-bound intermediate affects the entropy-enthalpy compensation of inhibitor-PR interaction.

scholarly journals Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Masayuki Amano ◽  
Pedro Miguel Salcedo-Gómez ◽  
Ravikiran S. Yedidi ◽  
Rui Zhao ◽  
Hironori Hayashi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protease Inhibitors ◽  
Multidrug Resistant ◽  
Strong Hydrogen Bond ◽  
Term Therapy ◽  
Wild Type ◽  
Hiv 1 ◽  
Cns Targeting

ABSTRACT There is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF), with a sulfonamide isostere, are highly active against wild-type HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0002 to ∼0.003 μM), with minimal cytotoxicity. These CNS-targeting PIs efficiently suppressed the replication of HIV-1 variants (EC50, 0.002 to ∼0.047 μM) that had been selected to propagate at high concentrations of conventional HIV-1 PIs. Such CNS-targeting PIs maintained their antiviral activity against HIV-2ROD as well as multidrug-resistant clinical HIV-1 variants isolated from AIDS patients who no longer responded to existing antiviral regimens after long-term therapy. Long-term drug selection experiments revealed that the emergence of resistant-HIV-1 against these CNS-targeting PIs was substantially delayed. In addition, the CNS-targeting PIs showed the most favorable CNS penetration properties among the tested compounds, including various FDA-approved anti-HIV-1 drugs, as assessed with the in vitro blood-brain barrier reconstruction system. Crystallographic analysis demonstrated that the bicyclic rings at the P2 moiety of the CNS-targeting PIs form strong hydrogen-bond interactions with HIV-1 protease (PR) active site. Moreover, both the P1-3,5-bis-fluorophenyl and P1-para-monofluorophenyl rings sustain greater van der Waals contacts with PR than in the case of darunavir (DRV). The data suggest that the present CNS-targeting PIs have desirable features for treating patients infected with wild-type and/or multidrug-resistant HIV-1 strains and might serve as promising preventive and/or therapeutic candidates for HIV-1-associated neurocognitive disorders (HAND) and other CNS complications.

Fluorine-Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier (BBB) Penetration Property of Novel Central Nervous System (CNS)-targeting HIV-1 Protease Inhibitors In Vitro .

2022 ◽  
Author(s):  
Masayuki Amano ◽  
Ravikiran S. Yedidi ◽  
Pedro Miguel Salcedo-Gómez ◽  
Hironori Hayashi ◽  
Kazuya Hasegawa ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Blood Brain Barrier ◽  
Drug Resistant ◽  
Wild Type ◽  
Hiv 1 ◽  
Cns Targeting

To date, there are no specific treatment regimens for the HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). In the present study, we report that two newly generated CNS-targeting HIV-1 protease inhibitors (PIs), GRL-08513 and GRL-08613, which have P1-3,5- bis -fluorophenyl- or P1- para -monofluorophenyl-ring, and P2-tetrahydropyrano-tetrahydrofuran ( Tp -THF) with a sulfonamide isostere, are potent against wild-type HIV-1s and multiple clinically isolated HIV-1s (EC 50 : 0.0001∼0.0032 μM). As assessed with HIV-1 variants that had been selected in vitro to propagate at 5 μM concentration of each HIV-1 PI (atazanavir, lopinavir, or amprenavir), GRL-08513 and GRL-08613 efficiently inhibited the replication of these highly-PI-resistant variants (EC 50 : 0.003∼0.006 μM). GRL-08513 and GRL-08613 also maintained their antiviral activity against HIV-2 ROD as well as severe multi-drug-resistant clinical HIV-1 variants. Additionally, when we assessed with the in vitro blood-brain barrier (BBB) reconstruction system, GRL-08513 and GRL-08613 showed the most promising properties of CNS-penetration among the evaluated compounds including the majority of FDA-approved cART drugs. In the crystallographic analysis of compound-protease (PR) complexes, it was demonstrated that the Tp -THF rings at the P2 moiety of GRL-08513 and GRL-08613 form robust hydrogen-bond interactions with the active-site of HIV-1 PR. Furthermore, both the P1-3,5- bis -fluorophenyl- and P1- para -monofluorophenyl-rings sustain greater contact surfaces and form stronger van der Waals interactions with PR compared to the case of darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for the patients infected with wild-type/multi-drug-resistant HIV-1s, and might serve as candidates of preventive and/or therapeutic for HAND and other CNS complications.

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