Limits...
HIV-1 Integrase Strand Transfer Inhibitorswith Reduced Susceptibility to Drug Resistant Mutant Integrases

View Article: PubMed Central - PubMed

ABSTRACT

HIVintegrase (IN) strand transfer inhibitors (INSTIs) are amongthe newest anti-AIDS drugs; however, mutant forms of IN can conferresistance. We developed noncytotoxic naphthyridine-containing INSTIsthat retain low nanomolar IC50 values against HIV-1 variantsharboring all of the major INSTI-resistant mutations. We found byanalyzing crystal structures of inhibitors bound to the IN from theprototype foamy virus (PFV) that the most successful inhibitors showstriking mimicry of the bound viral DNA prior to 3′-processingand the bound host DNA prior to strand transfer. Using this conceptof “bi-substrate mimicry,” we developed a new broadlyeffective inhibitor that not only mimics aspects of both the boundtarget and viral DNA but also more completely fills the space theywould normally occupy. Maximizing shape complementarity and recapitulatingstructural components encompassing both of the IN DNA substrates couldserve as a guiding principle for the development of new INSTIs.

No MeSH data available.


Compound 4c in the active site of the PFV intasome.(A) Superposition of the binding of 4c (blue) with pre-3′-processedDNA (carbons in gold; PDB code: 4E7I(25)) and targetDNA (carbons in black; PDB code: 4E7K(25)). The basesof proximal nucleotides of the viral and host DNAs are annotated.The hydrogen bond between the 6- substituent terminal hydroxyl of 4c with the backbone amide nitrogen of Tyr212 is shown. (B)Closeup of panel A highlighting regions of correspondence betweenthe 6-side chain of 4c and the nucleotides of the substrateDNAs: red, phosphoryl oxygens; yellow, T+2 deoxysugar;and green, G–1 deoxysugar. The IN residue Tyr212is not shown for clarity.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4836387&req=5

fig3: Compound 4c in the active site of the PFV intasome.(A) Superposition of the binding of 4c (blue) with pre-3′-processedDNA (carbons in gold; PDB code: 4E7I(25)) and targetDNA (carbons in black; PDB code: 4E7K(25)). The basesof proximal nucleotides of the viral and host DNAs are annotated.The hydrogen bond between the 6- substituent terminal hydroxyl of 4c with the backbone amide nitrogen of Tyr212 is shown. (B)Closeup of panel A highlighting regions of correspondence betweenthe 6-side chain of 4c and the nucleotides of the substrateDNAs: red, phosphoryl oxygens; yellow, T+2 deoxysugar;and green, G–1 deoxysugar. The IN residue Tyr212is not shown for clarity.

Mentions: Next, we determined the structure of the PFV intasome crystallizedwith the 6-substituted compound 4c (Figure 3). The structure revealed thatthe hydroxyl group of the pentan-5-ol side chain of 4c forms a hydrogen bond with the backbone amide of PFV IN Tyr212,a residue that corresponds to HIV-1 IN Tyr143 (Figure 3A). Of particular interest, this same amidegroup interacts with the phosphoryl groups of both the viral and targetDNAs during the 3′-P and ST reactions, respectively.25 Until now, RAL was the only INSTI known to makeinteractions with the backbone amide of Tyr143. However, in case ofRAL, the interaction depends on the stacking of its 1,3,4-oxadiazolering with the side chain of Tyr143, making the drug highly susceptibleto the Y143R mutation.18,19,32


HIV-1 Integrase Strand Transfer Inhibitorswith Reduced Susceptibility to Drug Resistant Mutant Integrases
Compound 4c in the active site of the PFV intasome.(A) Superposition of the binding of 4c (blue) with pre-3′-processedDNA (carbons in gold; PDB code: 4E7I(25)) and targetDNA (carbons in black; PDB code: 4E7K(25)). The basesof proximal nucleotides of the viral and host DNAs are annotated.The hydrogen bond between the 6- substituent terminal hydroxyl of 4c with the backbone amide nitrogen of Tyr212 is shown. (B)Closeup of panel A highlighting regions of correspondence betweenthe 6-side chain of 4c and the nucleotides of the substrateDNAs: red, phosphoryl oxygens; yellow, T+2 deoxysugar;and green, G–1 deoxysugar. The IN residue Tyr212is not shown for clarity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836387&req=5

fig3: Compound 4c in the active site of the PFV intasome.(A) Superposition of the binding of 4c (blue) with pre-3′-processedDNA (carbons in gold; PDB code: 4E7I(25)) and targetDNA (carbons in black; PDB code: 4E7K(25)). The basesof proximal nucleotides of the viral and host DNAs are annotated.The hydrogen bond between the 6- substituent terminal hydroxyl of 4c with the backbone amide nitrogen of Tyr212 is shown. (B)Closeup of panel A highlighting regions of correspondence betweenthe 6-side chain of 4c and the nucleotides of the substrateDNAs: red, phosphoryl oxygens; yellow, T+2 deoxysugar;and green, G–1 deoxysugar. The IN residue Tyr212is not shown for clarity.
Mentions: Next, we determined the structure of the PFV intasome crystallizedwith the 6-substituted compound 4c (Figure 3). The structure revealed thatthe hydroxyl group of the pentan-5-ol side chain of 4c forms a hydrogen bond with the backbone amide of PFV IN Tyr212,a residue that corresponds to HIV-1 IN Tyr143 (Figure 3A). Of particular interest, this same amidegroup interacts with the phosphoryl groups of both the viral and targetDNAs during the 3′-P and ST reactions, respectively.25 Until now, RAL was the only INSTI known to makeinteractions with the backbone amide of Tyr143. However, in case ofRAL, the interaction depends on the stacking of its 1,3,4-oxadiazolering with the side chain of Tyr143, making the drug highly susceptibleto the Y143R mutation.18,19,32

View Article: PubMed Central - PubMed

ABSTRACT

HIVintegrase (IN) strand transfer inhibitors (INSTIs) are amongthe newest anti-AIDS drugs; however, mutant forms of IN can conferresistance. We developed noncytotoxic naphthyridine-containing INSTIsthat retain low nanomolar IC50 values against HIV-1 variantsharboring all of the major INSTI-resistant mutations. We found byanalyzing crystal structures of inhibitors bound to the IN from theprototype foamy virus (PFV) that the most successful inhibitors showstriking mimicry of the bound viral DNA prior to 3′-processingand the bound host DNA prior to strand transfer. Using this conceptof “bi-substrate mimicry,” we developed a new broadlyeffective inhibitor that not only mimics aspects of both the boundtarget and viral DNA but also more completely fills the space theywould normally occupy. Maximizing shape complementarity and recapitulatingstructural components encompassing both of the IN DNA substrates couldserve as a guiding principle for the development of new INSTIs.

No MeSH data available.