Peptide Triazole Inactivators of HIV-1: How Do They Work and What is Their Potential?

Chaiken, Irwin M.; Rashad, Adel A.

doi:10.4155/fmc.15.152

Cited by 9 publications

(8 citation statements)

References 25 publications

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“…20 They exert this unique mode of inactivation by hijacking the metastability of the Env protein complex, 21 converting the gp120 into an inactive conformation that leads to gp120 shedding off the Env from the virion surface. 20 The resultant gp41 coated virions become non-infectious.…”

Section: Introductionmentioning

confidence: 99%

Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring

et al. 2017

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HIV-1 entry inhibition remains an urgent need for AIDS drug discovery and development. We previously reported the discovery of cyclic peptide triazoles (cPTs) that retain the HIV-1 irreversible inactivation functions of the parent linear peptides (PTs) and have massively increased proteolytic resistance. Here, in an initial structure-activity relationship investigation, we evaluated the effects of variations in key structural and functional components of the cPT scaffold in order to produce a platform for developing next-generation cPTs. Some structural elements, including stereochemistry around the cyclization residues and Ile and Trp side chains in the gp120-binding pharmacophore, exhibited relatively low tolerance for change, reflecting the importance of these components for function. In contrast, in the pharmacophore-central triazole position, the ferrocene moiety could be successfully replaced with smaller aromatic rings, where a p-methyl-phenyl methylene moiety gave cPT 24 with an IC50 value of 180 nM. Based on the observed activity of the biphenyl moiety when installed on the triazole ring (cPT 23, IC50 ∼ 269 nM), we further developed a new on-resin synthetic method to easily access the bi-aryl system during cPT synthesis, in good yields. A thiophene-containing cPT AAR029N2 (36) showed enhanced entropically favored binding to Env gp120 and improved antiviral activity (IC50 ∼ 100 nM) compared to the ferrocene-containing analogue. This study thus provides a crucial expansion of chemical space in the pharmacophore to use as a starting point, along with other allowable structural changes, to guide future optimization and minimization for this important class of HIV-1 killing agents.

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Section: Introductionmentioning

confidence: 99%

Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring

et al. 2017

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Section: Hiv-entry Inhibitorsmentioning

confidence: 99%

“…Peptidomimetics of peptide triazole provide a model that enhances the activity of PTs and helps in the development of HIV-1 inactivators that can prevent HIV entry into host cells. 124,125 C-peptides, obtained from the C-terminal heptad repeat 2 (HR2) region of the HIV-1 gp41, are a potent fusion inhibitor. They prevent gp41 NHR-CHR interaction by binding to the coiled N-peptide region, which is transiently exposed in the prehairpin intermediate state.…”

Section: Hiv-entry Inhibitorsmentioning

confidence: 99%

Therapeutic potential of HIV-1 entry inhibitor peptidomimetics

Korie

Tandoh

Kwofie

et al. 2021

Exp Biol Med (Maywood)

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Human immunodeficiency virus 1 (HIV-1) infection remains a public health concern globally. Although great strides in the management of HIV-1 have been achieved, current highly active antiretroviral therapy is limited by multidrug resistance, prolonged use-related effects, and inability to purge the HIV-1 latent pool. Even though novel therapeutic options with HIV-1 broadly neutralizing antibodies (bNAbs) are being explored, the scalability of bNAbs is limited by economic cost of production and obligatory requirement for parenteral administration. However, these limitations can be addressed by antibody mimetics/peptidomimetics of HIV-1 bNAbs. In this review we discuss the limitations of HIV-1 bNAbs as HIV-1 entry inhibitors and explore the potential therapeutic use of antibody mimetics/peptidomimetics of HIV-1 entry inhibitors as an alternative for HIV-1 bNAbs. We highlight the reduced cost of production, high specificity, and oral bioavailability of peptidomimetics compared to bNAbs to demonstrate their suitability as candidates for novel HIV-1 therapy and conclude with some perspectives on future research toward HIV-1 novel drug discovery.

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“…In so doing, PT-based Env inactivators, can suppress virus proliferation from infected cells. This will open up exploring cellular effects of a recently-discovered class of metabolically-stable and high-potency macrocyclic PT Env inactivators (Chaiken and Rashad, 2015; Rashad et al, 2015). …”

Section: Breadth Of Aunp-kr13 and Kr13 Functions In Cells Producing Rmentioning

confidence: 99%

Targeting cell surface HIV-1 Env protein to suppress infectious virus formation

et al. 2017

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HIV-1 Env protein is essential for host cell entry, and targeting Env remains an important antiretroviral strategy. We previously found that a peptide triazole thiol KR13 and its gold nanoparticle conjugate AuNP-KR13 directly and irreversibly inactivate the virus by targeting the Env protein, leading to virus gp120 shedding, membrane disruption and p24 capsid protein release. Here, we examined the consequences of targeting cell-surface Env with the virus inactivators. We found that both agents led to formation of non-infectious virus from transiently transfected 293T cells. The budded non-infectious viruses lacked Env gp120 but contained gp41. Importantly, budded virions also retained the capsid protein p24, in stark contrast to p24 leakage from viruses directly treated by these agents and arguing that the agents led to deformed viruses by transforming the cells at a stage before virus budding. We found that the Env inactivators caused gp120 shedding from the transiently transfected 293T cells as well as non-producer CHO-K1-gp160 cells. Additionally, AuNP-KR13 was cytotoxic against the virus-producing 293T and CHO-K1-gp160 cells, but not untransfected 293T or unmodified CHO-K1 cells. The results obtained reinforce the argument that cell-surface HIV-1 Env is metastable, as on virus particles, and provides a conformationally vulnerable target for virus suppression and infectious cell inactivation.

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Peptide Triazole Inactivators of HIV-1: How Do They Work and What is Their Potential?

Cited by 9 publications

References 25 publications

Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring

Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring

Therapeutic potential of HIV-1 entry inhibitor peptidomimetics

Targeting cell surface HIV-1 Env protein to suppress infectious virus formation

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