Increase of anti-HIV activity of C-peptide fusion inhibitors using a bivalent drug design approach

Ling, Yanbo; Xue, Huifang; Jiang, Xifeng; Cai, Lifeng; Liu, Keliang

doi:10.1016/j.bmcl.2013.07.012

Cited by 7 publications

(5 citation statements)

References 20 publications

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“…During gp41-mediated HIV-1 infection, the NHR region forms a parallel trimeric coiled coil on the periphery of which three hydrophobic grooves become transiently exposed that can be targets for therapeutic intervention. Because the NHR-trimer contains three symmetric grooves, we and others have reported bivalent HIV-1 fusion inhibitors, in which two polypeptide chains could interact with two of the three NHR grooves, respectively, thereby eliciting cooperative effects. , Therefore, HP23 may bind to one of three grooves on the NHR-trimer, while hCS6ERE interacts with other unoccupied grooves, thus resulting in synergistic anti-HIV-1 effect.…”

Section: Resultsmentioning

confidence: 98%

“…Because the NHR-trimer contains three symmetric grooves, we and others have reported bivalent HIV-1 fusion inhibitors, in which two polypeptide chains could interact with two of the three NHR grooves, respectively, thereby eliciting cooperative effects. 46,47 Therefore, HP23 may bind to one of three grooves on the NHR-trimer, while hCS6ERE interacts with other unoccupied grooves, thus resulting in synergistic anti-HIV-1 effect. Next, we determined the inhibitory activity of hCS6ERE and HP23 against a panel of T20-and T2635-resistant strains.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Design and Biological Evaluation of m-Xylene Thioether-Stapled Short Helical Peptides Targeting the HIV-1 gp41 Hexameric Coiled–Coil Fusion Complex

Meng

et al. 2019

J. Med. Chem.

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Short peptide-based inhibition of fusion remains an attractive goal in antihuman immunodeficiency virus (HIV) research based on its potential for the development of technically and economically desirable antiviral agents. Herein, we report the use of the dithiol bisalkylation reaction to generate a series of m-xylene thioether-stapled 22-residue α-helical peptides that have been identified as fusion inhibitors targeting HIV-1 glycoprotein 41 (gp41). The peptide sequence is based on the helix-zone binding domain of the gp41 C-terminal heptad repeat region. We found that one of these stapled peptides, named hCS6ERE, showed promising inhibitory potency against HIV-1 Env-mediated cell−cell fusion and viral replication at a level comparable to the clinically used 36-mer peptide T20. Furthermore, combining hCS6ERE with a fusion inhibitor having a different target site, such as HP23, produced synergistic anti-HIV-1 activity. Collectively, our study offers new insight into the design of anti-HIV peptides with short sequences.

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Section: Resultsmentioning

confidence: 98%

Section: ■ Results and Discussionmentioning

confidence: 99%

Design and Biological Evaluation of m-Xylene Thioether-Stapled Short Helical Peptides Targeting the HIV-1 gp41 Hexameric Coiled–Coil Fusion Complex

Meng

et al. 2019

J. Med. Chem.

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“…Besides the approaches that associate the peptide inhibitors with cell membranes or serum albumin, other original strategies have involved peptide modications. For example, hybrid molecules of small-molecule fusion inhibitors covalently attached to C-peptide; 37 a chimeric peptide composed of two different target peptides 56 ; polymers; 57,32 and bivalent peptides 58 have been designed as novel drugs. The designs of these conjugates share one common idea, that is, to make several drug moieties synergistically work in one molecule and develop new drugs with higher potency than several drugs utilised together.…”

Section: Other Conjugatesmentioning

confidence: 99%

Peptide HIV fusion inhibitors: modifications and conjugations

et al. 2014

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HIV fusion inhibitors are a group of virus entry preventing drugs aimed at membrane fusion. Several peptide drugs are screened with potent capacity to block virus-host cell fusion efficiently, and researchers have begun to focus on peptide drug design. However, so far T-20 is the only fusion inhibitor that has been approved by the FDA and utilised in treating therapy-experienced AIDS patients. The application of conventional peptide drugs is often limited by their short in vivo half-life and heavy dose subcutaneous injection. Thus, it is necessary to design new types of peptides or alter the existing peptides in a modified form to reach lower EC 50 values and obtain longer in vivo half-lives. Here, we summarise the inhibitory mechanisms of peptide fusion inhibitors designed with anti-HIV potency. Also, we further discuss the recent achievement in these peptide derivatives. Several approaches have been applied to optimise the peptide properties, and we provide examples of successful peptide conjugation strategies to provide hints for additional peptide therapeutic design.

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“…17 Dimerization of 22 residue helical C-peptides improved activity by a factor of 9. 18 Similarly, D-peptides designed to bind in the hydrophobic pocket 19 have activity improved by 10 – 300 fold upon dimerization with a long polyethylene glycol (PEG) linker, presumably by simultaneous interactions in two HP’s of the trimer. 20, 21 …”

Section: Introductionmentioning

confidence: 99%

Enhanced potency of bivalent small molecule gp41 inhibitors

Sofiyev

Kaur

Snyder

et al. 2017

Bioorganic & Medicinal Chemistry

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Low molecular weight peptidomimetic inhibitors with hydrophobic pocket binding properties and moderate fusion inhibitory activity against HIV-1 gp41-mediated cell fusion were elaborated by increasing the available surface area for interacting with the heptad repeat-1 (HR1) coiled coil on gp41. Two types of modifications were tested: 1) increasing the overall hydrophobicity of the molecules with an extension that could interact in the HR1 groove, and 2) forming symmetrical dimers with two peptidomimetic motifs that could potentially interact simultaneously in two hydrophobic pockets on the HR1 trimer. The latter approach was more successful, yielding 40 – 60 times improved potency against HIV fusion over the monomers. Biophysical characterization, including equilibrium binding studies by fluorescence and kinetic analysis by Surface Plasmon Resonance, revealed that inhibitor potency was better correlated to off-rates than to binding affinity. Binding and kinetic data could be fit to a model of bidentate interaction of dimers with the HR1 trimer as an explanation for the slow off-rate, albeit with minimal cooperativity due to the highly flexible ligand structures. The strong cooperativity observed in fusion inhibitory activity of the dimers implied accentuated potency due to the transient nature of the targeted intermediate. Optimization of monomer, dimer or higher order structures has the potential to lead to highly potent non-peptide fusion inhibitors by targeting multiple hydrophobic pockets.

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Increase of anti-HIV activity of C-peptide fusion inhibitors using a bivalent drug design approach

Cited by 7 publications

References 20 publications

Design and Biological Evaluation of m-Xylene Thioether-Stapled Short Helical Peptides Targeting the HIV-1 gp41 Hexameric Coiled–Coil Fusion Complex

Design and Biological Evaluation of m-Xylene Thioether-Stapled Short Helical Peptides Targeting the HIV-1 gp41 Hexameric Coiled–Coil Fusion Complex

Peptide HIV fusion inhibitors: modifications and conjugations

Enhanced potency of bivalent small molecule gp41 inhibitors

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