Mechanism of Darunavir (DRV)'s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance.
Discussion: In contrast, a set of data compiled for NDA21-976/S003 and NDA21-976/S004 clearly indicates that 10 amino acid substitutions including L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V are the most prevalent (https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021976s003s004lbl.pdf).
Polymorphisms and Mutational Covariation Associated with Death in a Prospective Cohort of HIV/AIDS Patients Receiving Long-Term ART in China.
Result: Among these newly found mutations, 7 mutations (E6D, E35D, S37N, I93L, E169D, T200V, and T200E) were considered to be potential drug resistance mutations (Table 2).
Result: Others 13 (65%) (E6D, Q18H, E35D, S37N, T39A, K43E, S68N, I93L, E169D, Q197K, T200V, T200E and E224D) had not been previous
Identification of HIV Mutation as Diagnostic Biomarker through Next Generation Sequencing.
PMID: 27630839
2016
Journal of clinical and diagnostic research
Abstract: The common mutations were identified at genome locations 1908 and 2104 as missense and silent mutations respectively, conferring S37N and S3S found on aspartic protease and reverse transcriptase subunits.
Abstract: This was especially the case for, missense mutation S37N which could cause an amino acid change in viral proteases thus reducing the binding affinity of some protease inhibitors.
Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics.
Result: Comparison of the DRV-bound complexes of PRS17 and wild type PR/DRV shows a large conformational change in the hinge loop region (residues 34-42) associated with mutations E35D, M36I and S37N in PRS17 (Fig 3A).
Result: This inactive protease with active site D25N mutation has 22 other mutations (L10I, V11I, L23I, V32I, L33F, Figure: Conformational Changes in Hinge Loop Mutations E35D, M36I and S37N.
Conformational variation of an extreme drug resistant mutant of HIV protease.
PMID: 26397743
2015
Journal of molecular graphics & modelling
Method: Plasmid DNA encoding PR (subtype B of group M) with 20 mutations Q7K; L10F; I13V; I15V; D30N; V32I; L33F; E35D; M36I; S37N; I47V; I54L; Q58E; I62V; L63P; A71V; I84V; N88D; L89T and L90M (termed PR20) cloned between the Nde1 and BamH1 sites
Persistence of frequently transmitted drug-resistant HIV-1 variants can be explained by high viral replication capacity.
Extreme multidrug resistant HIV-1 protease with 20 mutations is resistant to novel protease inhibitors with P1'-pyrrolidinone or P2-tris-tetrahydrofuran.
PMID: 23590295
2013
Journal of medicinal chemistry
Introduction: Recently, we characterized a clinically derived HIV-1 protease (PR20) bearing 20 mutations [Q7K, L10F, I13V, I15V, D30N, V32I, L33F, E35D, M36I, S37N, I47V, I54L, Q58E, I62V, L63P, A71V, I84V, N88D, L89T and L90M] and extremely resist
Enhanced stability of monomer fold correlates with extreme drug resistance of HIV-1 protease.
5Result: Another multi-drug resistant mutant, MDR769 (PDB accession code ITW7) which exhibits a pronounced ""wide-open"" conformation of both flaps, also contains several of the substitutions seen in PR20: namely, S37N, I62V, I63P, A71V, I84V, and L90M."
HIV-1 protease with 20 mutations exhibits extreme resistance to clinical inhibitors through coordinated structural rearrangements.
Result: All the PR20 structures show the same large structural change in the flap hinge region (residues 34 to 43) relative to the corresponding wild-type PR structures, which is attributed in part to the E35D, M36I and S37N mutations (Figure 5A).
Crystallization of a non-B and a B mutant HIV protease.
Abstract: the subtype B mutant, with mutations Q7K, S37N, R41K, K45R, I54V, L63P, A71V, V82A and L90M, and the subtype F (wild type), naturally carrying mutations Q7K, I15V, E35D, M36I, S37N, R41K, R57K, D60E, Q61N, I62V, L63S, I64L and L89M, with res
HIV mutation literature information.
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