6UWB

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-08513


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 

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This is version 1.2 of the entry. See complete history


Literature

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

Amano, M.Yedidi, R.S.Salcedo-Gomez, P.M.Hayashi, H.Hasegawa, K.Martyr, C.D.Ghosh, A.K.Mitsuya, H.

(2022) Antimicrob Agents Chemother 66: e0171521-e0171521

  • DOI: https://doi.org/10.1128/AAC.01715-21
  • Primary Citation of Related Structures:  
    6UWB, 6UWC

  • PubMed Abstract: 

    To date, there are no specific treatment regimens for HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). Here, we report that two newly generated CNS-targeting HIV-1 protease (PR) inhibitors (PIs), GRL-08513 and GRL-08613, which have a 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-1 strains and multiple clinically isolated HIV-1 strains (50% effective concentration [EC 50 ]: 0.0001 to ∼0.0032 μM). As assessed with HIV-1 variants that had been selected in vitro to propagate at a 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 to ∼0.006 μM). GRL-08513 and GRL-08613 also maintained their antiviral activities against HIV-2 ROD as well as severely multidrug-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 combination antiretroviral therapy (cART) drugs. In the crystallographic analysis of compound-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 than is the case with darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for patients infected with wild-type/multidrug-resistant HIV-1 strains and might serve as candidates for a preventive and/or therapeutic agent for HAND and other CNS complications.


  • Organizational Affiliation

    Department of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Hospitalgrid.411152.2, Kumamoto, Kumamoto, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 0 
UniProt
Find proteins for P03367 (Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI))
Explore P03367 
Go to UniProtKB:  P03367
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03367
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
QJY (Subject of Investigation/LOI)
Query on QJY

Download Ideal Coordinates CCD File 
C [auth A](3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-yl {(2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-[(2-methylpropyl)({2-[(propan-2-yl)amino]-1,3-benzothiazol-6-yl}sulfonyl)amino]butan-2-yl}carbamate
C32 H42 F2 N4 O7 S2
QXYZQWZEXVYYJE-JMLJTDODSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.918α = 90
b = 62.918β = 90
c = 82.112γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-18
    Type: Initial release
  • Version 1.1: 2022-06-01
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Refinement description