HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases

Zhao, Xue Zhi; Smith, Steven J.; Maskell, Daniel P.; Métifiot, Mathieu; Pye, V.E.; Fesen, Katherine; Marchand, Christophe; Pommier, ﻿Yves; Cherepanov, Peter; Hughes, Stephen H.; Burke, Terrence R.

doi:10.1021/acschembio.5b00948

Cited by 35 publications

(118 citation statements)

References 45 publications

Supporting

Mentioning

117

Contrasting

Order By: Relevance

“…156 Furthermore, design of small molecules that more completely fill the substrate envelope within the intasome active site could lead to improved inhibitory properties. 358 …”

Section: Hiv-1 In As a Target For Drug Developmentmentioning

confidence: 99%

Retroviral DNA Integration

2016

Self Cite

View full text Add to dashboard Cite

The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications.

show abstract

“…156 Furthermore, design of small molecules that more completely fill the substrate envelope within the intasome active site could lead to improved inhibitory properties. 358 …”

Section: Hiv-1 In As a Target For Drug Developmentmentioning

confidence: 99%

Retroviral DNA Integration

2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Overlaying the structures of INSTI-bound PFV intasomes to those of the SSC and TCC yielded important insight into the mechanism of drug action (16,112,113). The RAL metalchelating oxygen atom distal from the halobenzyl group coincided with the nucleophilic water molecule for IN 3Ј processing activity (red sphere in Fig.…”

Section: Instismentioning

confidence: 99%

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

Engelman

2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Figure 3. Retroviral intasome structures. A-C, representative intasomes from the spumavirus PFV (A; protein database (PDB) accession code 3OY9), ␤-retrovirus MMTV (B; PDB code 3JCA), and lentivirus MVV (C; PDB code 5M0Q) are color-coded to highlight the CIC. Green and blue, catalytically active IN protomers; cyan, supporting IN CCDs; black, DNA strands. Whereas four PFV IN molecules suffice to form the CIC, both MMTV and MVV require six IN protomers. For MMTV, critical CTDs (magenta) are donated by flanking IN dimers, leading to an overall IN octamer. In MVV, flanking IN tetramers provide the critical CTDs, resulting in an overall IN hexadecamer. Gray coloring in B and C deemphasizes IN elements that do not compose the CIC. D-F, resected CCD and CTD domains from above green IN protomers, oriented to highlight the different CCD-CTD linker regions (dark gray). Associated magenta CTDs from separate IN protomers in E and F assume similar positions as the green CTD in D. Red sticks, DDE catalytic triad residues. JBC REVIEWS: HIV integrase mechanisms and inhibition 15140 Figure 4. INSTI structures and ALLINI chemotypes. A, diagrams of the four FDA-licensed INSTIs as well as investigational second-generation compound 6p (113, 119). B, representative ALLINI chemotypes. Asterisks mark common positions of t-butoxyacid moieties. JBC REVIEWS: HIV integrase mechanisms and inhibition 15142

show abstract

“…Antiviral activities of DTG and our compounds against a panel of INSTIresistant single mutants. We previously measured the antiviral potencies of DTG and 4c, 4d, 4f, 6b, and 6p in single-round replication assays using WT HIV-1, well-established first-generation INSTI-resistant mutants, and selected putative DTG-resistant mutants (18,19). However, we had not previously determined the 50% effective concentrations (EC 50 s) for DTG and our compounds against many of the emerging INSTI-resistant mutants that have recently been identified in cell culture selection studies and clinical trials (10,30,31).…”

Section: Resultsmentioning

confidence: 99%

“…4c and 4d include alcohol-derived attachments, 4f is a disulfonophenyl derivative (19), and 6b and 6p contain ester-derived substituents (18). All of the compounds potently inhibit the replication of WT HIV-1, and we showed that the best of these compounds retain their potency against a number of the well-known INSTI-resistant mutants (18,19). That allowed us to choose the most promising of our new compounds for detailed analysis.…”

mentioning

confidence: 83%

“…The importance of the oxazinane ring was clarified by superposing the structure of the prototype foamy virus (PFV) intasome with DTG bound onto the structure of the PFV intasome with a target DNA (tDNA) bound (16,17). This comparison showed that the oxazinane ring of DTG mimics aspects of the bound host DNA substrate (18,19). Because IN needs to be able to bind its DNA substrates, mutations that would interfere with binding of the oxazinane ring of DTG are also likely to interfere with binding of the host DNA substrate.…”

mentioning

confidence: 99%

See 1 more Smart Citation

HIV-1 Integrase Inhibitors That Are Broadly Effective against Drug-Resistant Mutants

Smith

Zhao

Burke

et al. 2018

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Integrase strand transfer inhibitors (INSTIs) have emerged as clinically effective therapeutics that inhibit HIV-1 replication by blocking the strand transfer reaction catalyzed by HIV-1 integrase (IN). Of the three FDA-approved INSTIs, dolutegravir (DTG) is the least apt to select for resistance. However, recent salvage therapy regimens had low response rates with therapies that included DTG, suggesting that DTG resistance can be selected in patients. Using a single-round infection assay, we evaluated a collection of our best inhibitors and DTG against a broad panel of INSTI-resistant mutants. Two of the new compounds, 4c and 4d, had antiviral profiles against the mutants we tested superior to that of DTG. The susceptibility profiles of 4c and 4d suggest that the compounds are candidates for development as INSTIs. Modeling the binding of 4d to HIV-1 IN reinforced the significance of mimicking the DNA substrate in developing compounds that are broadly effective in their abilities to inhibit HIV-1 INs with mutations in the active site.

show abstract

HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases

Cited by 35 publications

References 45 publications

Retroviral DNA Integration

Retroviral DNA Integration

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

HIV-1 Integrase Inhibitors That Are Broadly Effective against Drug-Resistant Mutants

Contact Info

Product

Resources

About