GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions

Šašková, Klára Grantz; Kožíšek, Milan; Stray, Kirsten M.; Jong, Dorien de; Řezáčová, P.; Brynda, J.; Maarseveen, Noortje M van; Nijhuis, Monique; Cihlář, Tomáš; Konvalinka, Jan

doi:10.1128/jvi.02688-13

Cited by 9 publications

(3 citation statements)

References 21 publications

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“…This phosphonate ‘solvent anchor’ may be responsible for the retention of antiviral activity against resistant variants as measured by ITC. Recently, the structure of GS-8374 was reported in complex with an unusual variant bearing 12 substitutions and a Glu-Glu insertion after Glu35 that is resistant to many drugs [68]. Their analysis suggests that retention of antiviral activity against this mutant is due to the ability of the P1 aromatic phosphonate to rearrange within the expanded cavity walls while remaining anchored to the solvent.…”

Section: Investigational Antiviral Inhibitorsmentioning

confidence: 99%

Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

2015

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The virally encoded protease is an important drug target for AIDS therapy. Despite the potency of the current drugs, infections with resistant viral strains limit the long-term effectiveness of therapy. Highly resistant variants of HIV protease from clinical isolates have different combinations of about 20 mutations and several orders of magnitude worse binding affinity for clinical inhibitors. Strategies are being explored to inhibit these highly resistant mutants. The existing inhibitors can be modified by introducing groups with the potential to form new interactions with conserved protease residues, and the flexible flaps. Alternative strategies are discussed, including designing inhibitors to bind to the open conformation of the protease dimer, and inhibition of the protease-catalyzed processing of the Gag-Pol precursor.

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Section: Investigational Antiviral Inhibitorsmentioning

confidence: 99%

Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

2015

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“…So far ten protease inhibitors have been approved by Food and Drug Administration (FDA), including squinavir (SQV), ritonavir (RTV), lopnavir (LPV), atazanavir (ATV), nelfinavir (NFV), indinavir (IDV), tipranavir (TPV), amprenavir (APV), fosamprenavir (FPV, prodrug of amprenavir), and darunavir (DRV or named as TMC114) 19 20 21 22 . These inhibitors bind to the active site of HIV-1 PR, block gag-pol, and thereby prevent the formation of mature virus particles in vitro .…”

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confidence: 99%

Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir

Wang

Shao

et al. 2015

Sci Rep

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Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The hydrophobic interactions between flap and 80 s (80’s) loop residues (mainly I50-I84’ and I50’-I84) play an important role in maintaining the closed conformation of HIV-1 protease. The double mutation in Act variant weakens the hydrophobic interactions, leading to the transition from closed to semi-open conformation of apo Act. APV or DRV binds with HIV-1 protease via both hydrophobic and hydrogen bonding interactions. The hydrophobic interactions from the inhibitor is aimed to the residues of I50 (I50’), I84 (I84’), and V82 (V82’) which create hydrophobic core clusters to further stabilize the closed conformation of flaps, and the hydrogen bonding interactions are mainly focused with the active site of HIV-1 protease. The combined change in the two kinds of protease-inhibitor interactions is correlated with the observed resistance mutations. The present study sheds light on the microscopic mechanism underlying the mutation effects on the dynamics of HIV-1 protease and the inhibition by APV and DRV, providing useful information to the design of more potent and effective HIV-1 protease inhibitors.

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“…Currently, there are ten PR inhibitors approved by the Food and Drug (FDA). They are saquinavir (SQV), ritonavir (RTV), indinavir (IDV), nelfinavir (NFV), amprenavir (APV), lopinavir (LPV), atazanavir (ATV), tipranavir (TPV), fosamprenavir (FPV, prodrug of amprenavir) and darunavir (DRV) 8 9 10 11 12 . Several more inhibitors are in late stages of clinical development.…”

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confidence: 99%

Effect of polarization on HIV-1protease and fluoro-substituted inhibitors binding energies by large scale molecular dynamics simulations

Duan

Zhu

et al. 2017

Sci Rep

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Molecular dynamics simulations in explicit water are carried out to study the binding of six inhibitors to HIV-1 protease (PR) for up to 700 ns using the standard AMBER force field and polarized protein-specific charge (PPC). PPC is derived from quantum mechanical calculation for protein in solution and therefore it includes electronic polarization effect. Our results show that in all six systems, the bridging water W301 drifts away from the binding pocket in AMBER simulation. However, it is very stable in all six complexes systems using PPC. Especially, intra-protease, protease-inhibitor hydrogen bonds are dynamic stabilized in MD simulation. The computed binding free energies of six complexes have a significantly linear correlation with those experiment values and the correlation coefficient is found to be 0.91 in PPC simulation. However, the result from AMBER simulation shows a weaker correlation with the correlation coefficient of −0.51 due to the lack of polarization effect. Detailed binding interactions of W301, inhibitors with PR are further analyzed and discussed. The present study provides important information to quantitative understanding the interaction mechanism of PR-inhibitor and PR-W301 and these data also emphasizes the importance of both the electronic polarization and the bridging water molecule in predicting precisely binding affinities.

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GS-8374, a Prototype Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits Protease Mutants with Amino Acid Insertions

Cited by 9 publications

References 21 publications

Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

Highly Resistant HIV-1 Proteases and Strategies for Their Inhibition

Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir

Effect of polarization on HIV-1protease and fluoro-substituted inhibitors binding energies by large scale molecular dynamics simulations

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