HIV-1 protease substrate-groove: Role in substrate recognition and inhibitor resistance

Biochimie ◽  
2015 ◽  
Vol 118 ◽  
pp. 90-103 ◽  
Author(s):  
Gary S. Laco
Keyword(s):  
Substrate Recognition ◽  
Protease Substrate ◽  
Inhibitor Resistance ◽  
Hiv 1

Local and spatial factors determining HIV-1 protease substrate recognition

2001 ◽  
Vol 358 (2) ◽  
pp. 505-510 ◽  
Author(s):  
Stephane HAZEBROUCK ◽  
Valerie MACHTELINCKX-DELMAS ◽  
Jean-Jacques KUPIEC ◽  
Pierre SONIGO
Keyword(s):  
Amino Acids ◽  
Cleavage Site ◽  
Insertional Mutagenesis ◽  
Substrate Recognition ◽  
Enzymic Activity ◽  
Local Sequence ◽  
Protease Substrate ◽  
The Stability ◽  
Potential Cleavage Site ◽  
Hiv 1

Insertional mutagenesis of the Escherichia coli thymidylate synthase (TS) was used to address substrate recognition of HIV-1 protease in a well characterized structural context. By modifying the TS conformation while maintaining its enzymic activity, we investigated the influence of protein folding on protease–substrate recognition. A slight destabilization of the TS structure permitted the cleavage of a target site, which was resistant in the native TS. This result supports a dynamic interpretation of HIV-1 protease specificity. Exposure time of the potential cleavage site, which depends on the stability of the global conformation, must be compatible with the cleavage kinetics, which are determined by the local sequence. Cleavage specificity has been described as the consequence of cumulative interactions, globally favourable, between at least six amino acids around the cleavage site. To investigate influence of local sequence, we introduced insertions of variable lengths in two exposed loops of the TS. In both environments, insertion of only two amino acids could determine specific cleavage. We then inserted libraries of dipeptides naturally cleaved by the HIV-1 protease in order to assess the limitations of established classifications of substrates in different conformational contexts.

scholarly journals Local and spatial factors determining HIV-1 protease substrate recognition

2001 ◽  
Vol 358 (2) ◽  
pp. 505 ◽  
Author(s):  
Stephane HAZEBROUCK ◽  
Valerie MACHTELINCKX-DELMAS ◽  
Jean-Jacques KUPIEC ◽  
Pierre SONIGO
Keyword(s):  
Substrate Recognition ◽  
Spatial Factors ◽  
Protease Substrate ◽  
Hiv 1

scholarly journals An automated protocol for modelling peptide substrates to proteases

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Rodrigo Ochoa ◽  
Mikhail Magnitov ◽  
Roman A. Laskowski ◽  
Pilar Cossio ◽  
Janet M. Thornton
Keyword(s):  
Substrate Recognition ◽  
Accessible Surface Area ◽  
Conformational Sampling ◽  
Structural Determinants ◽  
Peptide Substrates ◽  
The Family ◽  
Protease Substrate ◽  
Peptide Complexes ◽  
Accessible Surface ◽  
Automated Protocol

Abstract Background Proteases are key drivers in many biological processes, in part due to their specificity towards their substrates. However, depending on the family and molecular function, they can also display substrate promiscuity which can also be essential. Databases compiling specificity matrices derived from experimental assays have provided valuable insights into protease substrate recognition. Despite this, there are still gaps in our knowledge of the structural determinants. Here, we compile a set of protease crystal structures with bound peptide-like ligands to create a protocol for modelling substrates bound to protease structures, and for studying observables associated to the binding recognition. Results As an application, we modelled a subset of protease–peptide complexes for which experimental cleavage data are available to compare with informational entropies obtained from protease–specificity matrices. The modelled complexes were subjected to conformational sampling using the Backrub method in Rosetta, and multiple observables from the simulations were calculated and compared per peptide position. We found that some of the calculated structural observables, such as the relative accessible surface area and the interaction energy, can help characterize a protease’s substrate recognition, giving insights for the potential prediction of novel substrates by combining additional approaches. Conclusion Overall, our approach provides a repository of protease structures with annotated data, and an open source computational protocol to reproduce the modelling and dynamic analysis of the protease–peptide complexes.

scholarly journals No difference in HIV-1 integrase inhibitor resistance between CSF and blood compartments

2021 ◽  
Author(s):  
Basma Abdi ◽  
Mouna Chebbi ◽  
Marc Wirden ◽  
Elisa Teyssou ◽  
Sophie Sayon ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Routine Care ◽  
Biological Data ◽  
Recombinant Form ◽  
Hiv Integrase ◽  
Resistance Mutations ◽  
Clinical Routine ◽  
Inhibitor Resistance ◽  
Hiv 1

Abstract Background Little is known about HIV-1 integrase inhibitor resistance in the CNS. Objectives This study aimed to evaluate integrase inhibitor resistance in CSF, as a marker of the CNS, and compare it with the resistance in plasma. Methods HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care. Results Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in the plasma of viraemic patients was 5.32 (3.85–5.80) and 3.59 (2.16–4.50) log10 copies/mL versus 4.79 (3.56–5.25) and 3.80 (2.68–4.33) log10 copies/mL in the CSF of ARV-naive and ARV-treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form being CRF02_AG (42.4%). The HIV-1 integrase sequences from CSF presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) for ARV-naive (L74I, n = 3; L74I/M, n = 1; T97A, n = 1; E157Q, n = 4) and ARV-treated (L74I, n = 6; L74M, n = 1; T97A, n = 1; N155H, n = 1) patients, respectively. Integrase inhibitor resistance mutations in CSF were similar to those in plasma, except for 1/59 patients. Conclusions This work shows similar integrase inhibitor resistance profiles in the CNS and plasma in a population of HIV-1 viraemic patients.

scholarly journals Performance of the Abbott RealTime HIV-1 Viral Load Assay Is Not Impacted by Integrase Inhibitor Resistance-Associated Mutations

2011 ◽  
Vol 49 (4) ◽  
pp. 1631-1634 ◽  
Author(s):  
T. P. Young ◽  
G. Cloherty ◽  
S. Fransen ◽  
L. Napolitano ◽  
P. Swanson ◽  
...  
Keyword(s):  
Viral Load ◽  
Integrase Inhibitor ◽  
Viral Load Assay ◽  
Inhibitor Resistance ◽  
Hiv 1

HIV-2 protease sequences of subtypes A and B harbor multiple mutations associated with protease inhibitor resistance in HIV-1

AIDS ◽  
2004 ◽  
Vol 18 (3) ◽  
pp. 495-502 ◽  
Author(s):  
Danuta Pieniazek ◽  
Mark Rayfield ◽  
Dale J Hu ◽  
John N Nkengasong ◽  
Vincent Soriano ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitor Resistance ◽  
Inhibitor Resistance ◽  
Hiv 1

Lack of impact of protease inhibitor resistance-associated mutations on the outcome of HIV-1-infected patients switching to darunavir-based dual therapy

2019 ◽  
Vol 52 (3) ◽  
pp. 202-206
Author(s):  
Pilar Vizcarra ◽  
José L. Blanco ◽  
Rocío Montejano ◽  
Eugenia Negredo ◽  
Nuria Espinosa ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Dual Therapy ◽  
Protease Inhibitor Resistance ◽  
Inhibitor Resistance ◽  
Hiv 1

Prevalence of integrase strand transfer inhibitor resistance mutations in antiretroviral-naive HIV-1-infected individuals in Cameroon

2020 ◽  
Vol 76 (1) ◽  
pp. 124-129
Author(s):  
Benjamin M Wenk ◽  
Herbert A Mbunkah ◽  
Ndi N Nsanwe ◽  
Eyongetah T Mbu ◽  
Lydia M Besong ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Universal Primers ◽  
Polymorphism Analysis ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Transfer Inhibitor ◽  
Study Sites ◽  
Inhibitor Resistance ◽  
The Impact ◽  
Hiv 1

Abstract Objectives In Cameroon, the integrase (IN) strand transfer inhibitor (INSTI) dolutegravir was recently introduced for the treatment of HIV-1 infection. Since pretreatment HIV-1 drug resistance can jeopardize the success of ART, and considering the high heterogeneity of circulating HIV-1 subtypes in Cameroon, we investigated the prevalence of pretreatment HIV-1 resistance to INSTIs. Methods Fingerprick dried blood spot samples were collected from 339 newly diagnosed HIV-1-infected individuals between 2015 and 2016 in four hospitals in Cameroon. Universal primers were designed to amplify the HIV-1 IN region from amino acid 1 to 276. Amplicons were sequenced with Illumina next-generation sequencing and analysed with the Polymorphism Analysis Sequencing (PASeq) platform, using the Stanford HIV Drug Resistance Database to interpret HIV-1 drug resistance mutations (DRMs). Results The amplification/sequencing success rate was 75.2% with 255/339 sequences obtained. Applying a cut-off of 1%, major DRMs to INSTIs were detected in 13 (5.1%) individuals, but only 1 individual harboured an INSTI DRM (E92G) at a nucleotide frequency ≥15%. However, 140/255 (54.9%) individuals harboured polymorphic accessory INSTI DRMs, mainly at high frequencies. In line with that observation, HIV-1 subtype diversity among individuals was high. Conclusions Pretreatment HIV-1 resistance to INSTIs was low in the study sites, which supports the use of INSTIs in Cameroon. Nevertheless, further studies are necessary to assess the impact of polymorphic accessory INSTI DRMs on INSTI-based ART regimens.

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