Performance of Affinity-Improved DARPin Targeting HIV Capsid Domain in Interference of Viral Progeny Production

Sornsuwan, Kanokporn; Thongkhum, Weeraya; Pamonsupornwichit, Thanathat; Carraway, Tanawan Samleerat; Soponpong, Suthinee; Sakkhachornphop, Supachai; Tayapiwatana, Chatchai; Yasamut, Umpa

doi:10.3390/biom11101437

Cited by 4 publications

(8 citation statements)

References 52 publications

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“…Ank GAG 1D4-S45Y mutant as a specific CAp24 domain inhibitor of HIV-1 Gag was constructed using sited-direct mutagenesis. The binding affinity of Ank GAG 1D4-S45Y mutant (KD = 45 nM) was partly enhanced and inhibited either HIV-1 wild-type or the HIV maturation inhibitor-resistant strain for intracellular activity compared to parental Ank GAG 1D4 (KD = 109 nM) [ 6 , 7 ]. Dimeric Ank GAG 1D4 was generated to further improve its binding activity and evaluated for the binding activity [ 11 ] ( Figure S1 ).…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon confers the potential of Ank GAG 1D4 NC-CN to interfere with HIV-1 Gag-assemble compared to Ank GAG 1D4 NC-NC and monomeric Ank GAG 1D4. Previously, an anti-HIV-1 production of Ank GAG 1D4-S45Y has been expressed, and the leakage of HIV-1 virions production was detected in the late infection [ 7 ]. Although Ank GAG 1D4-S45Y enhanced anti-HIV-1 activity, both dimeric ankyrins were superior.…”

Section: Discussionmentioning

confidence: 99%

“…According to the bio-layer interferometry (BLI) experiment, Ank GAG 1D4-S45Y mutant successfully improved the binding affinity compared to Ank GAG 1D4 [ 6 ]. Likewise, Ank GAG 1D4-S45Y markedly inhibits HIV-1 wild-type and the HIV-1 maturation inhibitor-resistant (MIR) strain in SupT1 cells [ 7 ]. However, viral escape was observed in late infection.…”

Section: Introductionmentioning

confidence: 99%

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Dimeric Ankyrin with Inverted Module Promotes Bifunctional Property in Capturing Capsid to Impede HIV-1 Replication

Juntit

Sornsuwan

Wisitponchai

et al. 2023

IJMS

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Several anti-HIV scaffolds have been proposed as complementary treatments to highly active antiretroviral therapy. AnkGAG1D4, a designed ankyrin repeat protein, formerly demonstrated anti-HIV-1 replication by interfering with HIV-1 Gag polymerization. However, the improvement of the effectiveness was considered. Recently, the dimeric molecules of AnkGAG1D4 were accomplished in enhancing the binding activity against HIV-1 capsid (CAp24). In this study, the interaction of CAp24 against the dimer conformations was elucidated to elaborate the bifunctional property. The accessibility of the ankyrin binding domains was inspected by bio-layer interferometry. By inverting the second module of dimeric ankyrin (AnkGAG1D4NC-CN), the CAp24 interaction KD was significantly reduced. This reflects the capability of AnkGAG1D4NC-CN in simultaneously capturing CAp24. On the contrary, the binding activity of dimeric AnkGAG1D4NC-NC was indistinguishable from the monomeric AnkGAG1D4. The bifunctional property of AnkGAG1D4NC-CN was subsequently confirmed in the secondary reaction with additional p17p24. This data correlates with the MD simulation, which suggested the flexibility of the AnkGAG1D4NC-CN structure. The CAp24 capturing capacity was influenced by the distance of the AnkGAG1D4 binding domains to introduce the avidity mode of AnkGAG1D4NC-CN. Consequently, AnkGAG1D4NC-CN showed superior potency in interfering with HIV-1 NL4-3 WT and HIV-1 NL4-3 MIRCAI201V replication than AnkGAG1D4NC-NC and an affinity improved AnkGAG1D4-S45Y.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dimeric Ankyrin with Inverted Module Promotes Bifunctional Property in Capturing Capsid to Impede HIV-1 Replication

Juntit

Sornsuwan

Wisitponchai

et al. 2023

IJMS

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“…SupT1 cells that stably express an artificial ankyrin repeat molecule (AnkGAG1D4) binding to the human immunodeficiency virus (HIV) Gag polyprotein showed a reduced permissiveness to HIV-1 infection [ 34 ]. Subsequent studies investigated the molecular mechanisms whereby AnkGAG1D4 inhibited HIV replication, showing that the intracellular expression of AnkGAG1D4 affected the late stages of virus production [ 66 , 67 , 68 , 69 ]. Despite this as a promising strategy, intracellular DARPin delivery may limit in vivo administration of the molecule.…”

Section: Viral Applicationsmentioning

confidence: 99%

Designed Ankyrin Repeat Proteins: A New Class of Viral Entry Inhibitors

Walser

Mayor

Rothenberger

2022

Viruses

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Designed ankyrin repeat proteins (DARPins) are engineered proteins comprising consensus designed ankyrin repeats as scaffold. Tightly packed repeats form a continuous hydrophobic core and a large groove-like solvent-accessible surface that creates a binding surface. DARPin domains recognizing a target of interest with high specificity and affinity can be generated using a synthetic combinatorial library and in vitro selection methods. They can be linked together in a single molecule to build multispecific and multifunctional proteins without affecting expression or function. The modular architecture of DARPins offers unprecedented possibilities of design and opens avenues for innovative antiviral strategies.

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“…Lipodystrophy and other metabolic abnormalities are most familiar with PI’s and to a lesser extent with other NRTIs, especially Stavudine (d4T). Certain fatty tissue anomalies appear to be associated with this older class of ARTs [ 93 , 94 ]. Fat misdistribution and changes in body habitus, hyperlipidemia, hyperglycemia, insulin resistance, and diabetes mellitus are indeed abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Novel Nanotechnology-Based Approaches for Targeting HIV Reservoirs

et al. 2022

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Highly active anti-retroviral therapy (HAART) is prescribed for HIV infection and, to a certain extent, limits the infection’s spread. However, it cannot completely eradicate the latent virus in remote and cellular reservoir areas, and due to the complex nature of the infection, the total eradication of HIV is difficult to achieve. Furthermore, monotherapy and multiple therapies are not of much help. Hence, there is a dire need for novel drug delivery strategies that may improve efficacy, decrease side effects, reduce dosing frequency, and improve patient adherence to therapy. Such a novel strategy could help to target the reservoir sites and eradicate HIV from different biological sanctuaries. In the current review, we have described HIV pathogenesis, the mechanism of HIV replication, and different biological reservoir sites to better understand the underlying mechanisms of HIV spread. Further, the review deliberates on the challenges faced by the current conventional drug delivery systems and introduces some novel drug delivery strategies that have been explored to overcome conventional drug delivery limitations. In addition, the review also summarizes several nanotechnology-based approaches that are being explored to resolve the challenges of HIV treatment by the virtue of delivering a variety of anti-HIV agents, either as combination therapies or by actively targeting HIV reservoir sites.

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Performance of Affinity-Improved DARPin Targeting HIV Capsid Domain in Interference of Viral Progeny Production

Cited by 4 publications

References 52 publications

Dimeric Ankyrin with Inverted Module Promotes Bifunctional Property in Capturing Capsid to Impede HIV-1 Replication

Dimeric Ankyrin with Inverted Module Promotes Bifunctional Property in Capturing Capsid to Impede HIV-1 Replication

Designed Ankyrin Repeat Proteins: A New Class of Viral Entry Inhibitors

Novel Nanotechnology-Based Approaches for Targeting HIV Reservoirs

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