HIV-1 integrase strand transfer inhibitors: a review of current drugs, recent advances and drug resistance

Mbhele, Nokuzola; Chimukangara, Benjamin; Gordon, Michelle

doi:10.1016/j.ijantimicag.2021.106343

Cited by 51 publications

(18 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This implied that pyrimidinone was an important moiety for interaction with divalent metal ions. As the pyrimidinone derivative, raltegravir was initially approved by FDA in late 2007 as the first available agent targeted HIV integrase [35]. We considered Hit01 (raltegravir's derivative) as the hit compound and structured a compound database to detect more effective PA N endonuclease inhibitors.…”

Section: Molecular Docking Studymentioning

confidence: 99%

“…1 The docking scores of selected candidate (Hit07-Hit09 and Hit10-Hit12) were lower than Hit01, except Hit07 and Hit11. Furthermore, the estimated activity values of all compounds were more declined than Hit01 (estimated activity value was 1.16424 As the pyrimidinone derivative, raltegravir was initially approved by FDA in late 2007 as the first available agent targeted HIV integrase [35]. We considered Hit01 (raltegravir's derivative) as the hit compound and structured a compound database to detect more effective PAN endonuclease inhibitors.…”

Section: Hit11mentioning

confidence: 99%

See 1 more Smart Citation

Identification of Influenza PAN Endonuclease Inhibitors via 3D-QSAR Modeling and Docking-Based Virtual Screening

et al. 2021

View full text Add to dashboard Cite

Structural and biochemical studies elucidate that PAN may contribute to the host protein shutdown observed during influenza A infection. Thus, inhibition of the endonuclease activity of viral RdRP is an attractive approach for novel antiviral therapy. In order to envisage structurally diverse novel compounds with better efficacy as PAN endonuclease inhibitors, a ligand-based-pharmacophore model was developed using 3D-QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery Studio. As the training set, 25 compounds were taken to generate a significant pharmacophore model. The selected pharmacophore Hypo1 was further validated by 12 compounds in the test set and was used as a query model for further screening of 1916 compounds containing 71 HIV-1 integrase inhibitors, 37 antibacterial inhibitors, 131 antiviral inhibitors and other 1677 approved drugs by the FDA. Then, six compounds (Hit01–Hit06) with estimated activity values less than 10 μM were subjected to ADMET study and toxicity assessment. Only one potential inhibitory ‘hit’ molecule (Hit01, raltegravir’s derivative) was further scrutinized by molecular docking analysis on the active site of PAN endonuclease (PDB ID: 6E6W). Hit01 was utilized for designing novel potential PAN endonuclease inhibitors through lead optimization, and then compounds were screened by pharmacophore Hypo1 and docking studies. Six raltegravir’s derivatives with significant estimated activity values and docking scores were obtained. Further, these results certainly do not confirm or indicate the seven compounds (Hit01, Hit07, Hit08, Hit09, Hit10, Hit11 and Hit12) have antiviral activity, and extensive wet-laboratory experimentation is needed to transmute these compounds into clinical drugs.

show abstract

Section: Molecular Docking Studymentioning

confidence: 99%

Section: Hit11mentioning

confidence: 99%

Identification of Influenza PAN Endonuclease Inhibitors via 3D-QSAR Modeling and Docking-Based Virtual Screening

et al. 2021

View full text Add to dashboard Cite

show abstract

“… 8 The first generation INSTIs include raltegravir (RAL) and elvitegravir (EVG), and the second generation INSTIs include dolutegravir (DTG), bictegravir (BIC) and cabotegravir (CAB) which have better safety, tolerability, and higher genetic barriers to the emergence of drug resistance. 9–11 …”

Section: Introductionmentioning

confidence: 99%

Drug Resistance to HIV-1 Integrase Inhibitors Among Treatment-Naive Patients in Beijing, China

Yuan¹,

Q²,

Wang³

et al. 2022

PGPM

View full text Add to dashboard Cite

Introduction Integrase strand transfer inhibitors (INSTIs) are important drugs that are currently used as the first line treatment for HIV-1 patients. The aim of this study was to characterize HIV-1 INSTI mutations among ART-naive patients in Beijing from 2019–2021. Methods 865 ART-naive patients were enrolled in this study between January 2019 and June 2021 in Beijing. The amplification of the entire pol gene containing the reverse transcriptase, protease and integrase regions was performed using a validated In-house SBS method. HIV-1 subtypes and circulating recombinant forms (CRFs) were determined using the COMET online tool ( http://comet.retrovirology.lu ). Stanford HIV-1 drug resistance database (HIVdb version 8.9) was used to analyze the mutations. Results 865 HIV-1 pol sequences were successfully amplified and sequenced. Among them, no major INSTI-related mutations were identified, but 12 polymorphic accessory mutations were found. Two patients have E138A and G163R mutations respectively and both could cause low-level resistance to RAL and EVG. Furthermore, one patient having S230R mutation resulted in low-level resistance to RAL, EVG, DTG and BIC. Conclusion The prevalence of INSTIs mutations remains low, which demonstrated that INSTIs have good applicability currently in our city. Nevertheless, it is very important to monitor the INSTI-related mutations in Beijing.

show abstract

“…DTG possesses several remarkable benefits like a once-daily-dose, a high genetic obstacle to drug resistance, and reduced drug-drug interactions. It is well tolerated and metabolically compatible when compared to other classes of ARVs 6 . Since it is a BCS class II drug, it exhibits limited aqueous solubility of 95 mg/L at 25 °C.…”

Section: Introductionmentioning

confidence: 99%

In-vivo pharmacokinetic studies of Dolutegravir loaded spray dried Chitosan nanoparticles as milk admixture for paediatrics infected with HIV

Banudevi

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Dolutegravir (DTG) is an antiretroviral drug approved in the year 2013, and being categorized as a BCS-II molecule, it possesses solubility issues. In order to enhance the solubility and improve its bioavailability, DTG-loaded Chitosan nanoparticles (NPs) were synthesized utilizing spray drying technology. The developed nanoformulation was characterized for its physicochemical properties and investigated for the feasibility of its administration through an oral route along with milk/food as an admixture for paediatric antiretroviral therapy. The in vivo oral bioavailability studies were conducted in Balb-C mice, where the animals were treated with the selected formulation of DTG-loaded Chitosan NPs and compared to pure DTG. The NPs exhibited 2.5-fold increase in the Cmax (77.54 ± 7.93 μg/mL) when compared to the pure DTG (30.15 ± 8.06 μg/mL). This phenomenon was further reflected by the improved bioavailability of DTG (AUC: 678.3 ± 10.07 μg/h/mL) in the NPs administered to mice when compared to the AUC of animals administered with pure DTG (405.29 ± 7 μg/h/mL). Altogether, the research findings showed that Chitosan-based NPs were ideal carriers for oral administration of DTG along with milk and exhibited great potential to enhance the bioavailability of the drug and treatment adherence for paediatric HIV patients.

show abstract

HIV-1 integrase strand transfer inhibitors: a review of current drugs, recent advances and drug resistance

Cited by 51 publications

References 54 publications

Identification of Influenza PAN Endonuclease Inhibitors via 3D-QSAR Modeling and Docking-Based Virtual Screening

Identification of Influenza PAN Endonuclease Inhibitors via 3D-QSAR Modeling and Docking-Based Virtual Screening

Drug Resistance to HIV-1 Integrase Inhibitors Among Treatment-Naive Patients in Beijing, China

In-vivo pharmacokinetic studies of Dolutegravir loaded spray dried Chitosan nanoparticles as milk admixture for paediatrics infected with HIV

Contact Info

Product

Resources

About