The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops

Kuiper, Benjamin; Keusch, Bradley; Dewdney, Tamaria G.; Chordia, Poorvi; Ross, K.; Brunzelle, J.S.; Kovari, Iulia A.; MacArthur, Rodger D.; Salimnia, Hossein; Kovari, Ladislau C.

doi:10.1016/j.bbrep.2015.06.003

Cited by 3 publications

(1 citation statement)

References 28 publications

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“…Actually, there are only three additional mutations present in the sequence of PR DRV R P51 : L33F, I54M and A82I, strongly suggesting that the substitution L33F is a major trigger for these rearrangements around the 30 s loop. Interestingly, PR DRV R P51 structure shows high similarities around 30 s loop with previous reported structure of HIV-1 protease with L33F mutation (PDB code: 4YOB) 23 . The larger side chain of Phe33 forms stronger hydrophobic interactions inside the hydrophobic cavity that pulls the whole 30 s loop towards the segment around Arg20 (Fig.…”

Section: Resultssupporting

confidence: 79%

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Bulut

Hattori

Aoki-Ogata

et al. 2020

Sci Rep

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HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2′-cyclopropylaminobenzothiazole (or-oxazole), and/or P1-benzene ring with fluorine scan of mono-or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PR Wt) and highly-multi-PI-resistance-associated PR DRV R P51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2′-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier. Over the last 3 decades, HIV-1 infection has remained a devastating disease with ~80 million people infected worldwide and nearly half of them have lost lives from the infection (https://www.avert.org/global-hiv-and-aids-statistics). However, the present combined antiretroviral therapy (cART) has been proven to potently suppress HIV-1 replication and to significantly prolong the survival of people with HIV-1 infection and AIDS. The inhibitors of HIV-1 protease (PR), an essential enzyme that cleaves gag and gag-pol polyproteins into mature functional proteins, are the key element of effective cART 1,2. Blocking the activity of PR leaves virions in an immature state, which are unable to infect cells, thus leading to restoration of the immune system 3. Currently, there are nine licensed HIV-1 protease inhibitors (PIs) with nanomolar ranges of inhibitory potency against wild type virus; however, none of them are able to eradicate the virus in the body 4,5. Moreover, drug-resistant HIV-1 variants often emerge during long-term therapy 6,7 , due to the error-prone virally-encoded reverse transcriptase (RT) 8. Darunavir (DRV) is a second-generation nonpeptidic PI, which is highly potent against wild-type HIV-1 (HIV WT) and has a high genetic barrier to the emergence of DRV-resistant variants, retaining its potent anti-HIV activity over long-term periods in clinical settings 9,10. Nevertheless, DRV-resistant variants have been reported

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Section: Resultssupporting

confidence: 79%

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Bulut

Hattori

Aoki-Ogata

et al. 2020

Sci Rep

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An insight to the molecular interactions of the FDA approved HIV PR drugs against L38L↑N↑L PR mutant

Sanusi

Govender

Maguire

et al. 2018

J Comput Aided Mol Des

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The aspartate protease of the human immune deficiency type-1 virus (HIV-1) has become a crucial antiviral target in which many useful antiretroviral inhibitors have been developed. However, it seems the emergence of new HIV-1 PR mutations enhances drug resistance, hence, the available FDA approved drugs show less activity towards the protease. A mutation and insertion designated L38L↑N↑L PR was recently reported from subtype of C-SA HIV-1. An integrated two-layered ONIOM (QM:MM) method was employed in this study to examine the binding affinities of the nine HIV PR inhibitors against this mutant. The computed binding free energies as well as experimental data revealed a reduced inhibitory activity towards the L38L↑N↑L PR in comparison with subtype C-SA HIV-1 PR. This observation suggests that the insertion and mutations significantly affect the binding affinities or characteristics of the HIV PIs and/or parent PR. The same trend for the computational binding free energies was observed for eight of the nine inhibitors with respect to the experimental binding free energies. The outcome of this study shows that ONIOM method can be used as a reliable computational approach to rationalize lead compounds against specific targets. The nature of the intermolecular interactions in terms of the host-guest hydrogen bond interactions is discussed using the atoms in molecules (AIM) analysis. Natural bond orbital analysis was also used to determine the extent of charge transfer between the QM region of the L38L↑N↑L PR enzyme and FDA approved drugs. AIM analysis showed that the interaction between the QM region of the L38L↑N↑L PR and FDA approved drugs are electrostatic dominant, the bond stability computed from the NBO analysis supports the results from the AIM application. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide information that will aid in the design of much improved HIV-1 PR antiviral drugs.

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Increased activity of unlinked Zika virus NS2B/NS3 protease compared to linked Zika virus protease

Kuiper

Slater

Spellmon

et al. 2017

Biochemical and Biophysical Research Communications

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Zika virus (ZIKV) is a flavivirus spread by daytime-active Aedes spp. mosquitoes such as A. aegypti and A. albopictus. Previously thought to be a mild infection, the latest ZIKV outbreak in the Americas is causally associated with more severe symptoms as well as severe birth defects, such as microcephaly. Currently no vaccine or antiviral exists. However, recent progress has demonstrated the viral NS2B/NS3 protease may be a suitable target for the development of small-molecule antiviral agents. To better understand the ZIKV protease, we expressed, purified, and characterized unlinked and linked NS2B/NS3 protease corresponding to an isolate from the recent outbreak in Puerto Rico. Unlinked ZIKV protease is more active and binds substrate with greater affinity than linked ZIKV protease. Therefore, we propose that unlinked ZIKV protease be used when evaluating or designing ZIKV protease inhibitors. Additionally, potent inhibitors of related viral proteases, like West Nile Virus and Dengue virus, may serve as advanced starting points to identify and develop ZIKV protease inhibitors.

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The L33F darunavir resistance mutation acts as a molecular anchor reducing the flexibility of the HIV-1 protease 30s and 80s loops

Cited by 3 publications

References 28 publications

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

An insight to the molecular interactions of the FDA approved HIV PR drugs against L38L↑N↑L PR mutant

Increased activity of unlinked Zika virus NS2B/NS3 protease compared to linked Zika virus protease

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