Macrocyclic Envelope Glycoprotein Antagonists that Irreversibly Inactivate HIV-1 <i>before</i> Host Cell Encounter

Rashad, Adel A.; Sundaram, Ramalingam Venkat Kalyana; Aneja, Rachna; Duffy, Caitlin; Chaiken, Irwin M.

doi:10.1021/acs.jmedchem.5b00935

Cited by 28 publications

(65 citation statements)

References 25 publications

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“…In this context, we have previously reported a class of small cyclic peptide triazoles (cPTs, represented by the first lead AAR029b 20 , 3 , Figure 1) that is able to irreversibly inactivate HIV-1 virions, even before host cell encounter. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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. Interestingly, the binding site of cPTs seems to overlap both binding sites of BMS-626529 and the CD4 small molecule mimetics.…”

Section: Introductionmentioning

confidence: 99%

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

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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%

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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“…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

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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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“…Inspired by the two-cavity model (Figure 4, left), we recently established a synthetic methodology to derive macrocyclic HIV-1 antagonists (Figure 4, right) [25]. The cyclic PTs (cPTs) retained the ability of the parent PTs to dually inhibit binding of gp120 at both its CD4 and coreceptor binding sites and induce gp120 shedding from the virions, leading to irreversible inactivation.…”

Section: Env Gp120 Cavity Occupancy Model and The Derivation Of Cyclic mentioning

confidence: 99%

“…The 6-residue cPT denoted AAR029b, the most active obtained so far, inhibited gp120 binding to both sCD4 and the core-ceptor surrogate, 17b, with IC 50 ~30 nM. AAR029b also inhibited cell infection by both BaL.01 and JR-FL pseudovirus strains with IC 50 values approximately 200 nM [25]. Importantly, these macrocycles were found to be stable to trypsin and chymotrypsin digestions, compared to a substantial susceptibility of corresponding linear PTs to these proteases.…”

Section: Env Gp120 Cavity Occupancy Model and The Derivation Of Cyclic mentioning

confidence: 99%

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

Chaiken

Rashad

2015

Future Med. Chem.

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Macrocyclic Envelope Glycoprotein Antagonists that Irreversibly Inactivate HIV-1 before Host Cell Encounter

Cited by 28 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

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

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

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