Evaluation of sequence variability in HIV-1 gp41 C-peptide helix-grafted proteins

Tennyson, Rachel L.; Walker, Susanne; Ikeda, Terumasa; Harris, Reuben S.; McNaughton, Brian R.

doi:10.1016/j.bmc.2017.07.064

Cited by 3 publications

(7 citation statements)

References 23 publications

(26 reference statements)

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“…In a recent study, this technology was used to screen the hits from a grafted C-peptide library of HIV gp41 against N-peptide trimer of HIVgp41. As a result, four hits suppressed the HIV entry better than others (Tennyson et al 2018).…”

Section: Yeast Displaymentioning

confidence: 99%

Antiviral Peptides: Identification and Validation

Agarwal

Gabrani

2020

Int J Pept Res Ther

109

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Despite rapid advances in the human healthcare, the infection caused by certain viruses results in high morbidity and mortality accentuate the importance for development of new antivirals. The existing antiviral drugs are limited, due to their inadequate response, increased rate of resistance and several adverse side effects. Therefore, one of the newly emerging field "peptide-based therapeutics" against viruses is being explored and seems promising. Over the last few years, a lot of scientific effort has been made for the identification of novel and potential peptide-based therapeutics using various advanced technologies. Consequently, there are more than 60 approved peptide drugs available for sale in the market of United States, Europe, Japan, and some Asian countries. Moreover, the number of peptide drugs undergoing the clinical trials is rising gradually year by year. The peptide-based antiviral therapeutics have been approved for the Human immunodeficiency virus (HIV), Influenza virus and Hepatitis virus (B and C). This review enlightens the various peptide sources and the different approaches that have contributed to the search of potential antiviral peptides. These include computational approaches, natural and biological sources (library based high throughput screening) for the identification of lead peptide molecules against their target. Further the applications of few advanced techniques based on combinatorial chemistry and molecular biology have been illustrated to measure the binding parameters such as affinity and kinetics of the screened interacting partners. The employment of these advanced techniques can contribute to investigate antiviral peptide therapeutics for emerging infections.

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Section: Yeast Displaymentioning

confidence: 99%

Antiviral Peptides: Identification and Validation

Agarwal

Gabrani

2020

Int J Pept Res Ther

109

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“…In the context of helix-grafted proteins, we have demonstrated these residues are necessary for recognition of 5-helix. 14 Thus, we avoided mutating these tryptophans in our library. In the firstgeneration of helix optimization, we mutated five residues (grafted and native) on the solvent-exposed face of the helix (EIYTI, light blue spheres, Figure 3a) to all 20 proteinogenic amino acids, generating a protein library of approximately 3.2 × 10 6 .…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

“…Yeast were induced to display the Sac7d-Cpep-based library, equipped with an N-terminal Myc tag. As in our prior work, 14 yeast were concomitantly incubated with a FITClabeled anti-Myc antibody and biotinylated gp41 5-helix. Following a brief washing step, streptavidin−phycoerythrin (SAV-PE) conjugate was added.…”

Section: Acs Infectious Diseasesmentioning

confidence: 99%

“…More recently, we showed that yeast display optimization of grafted residues on Cpep-ELMO led to proteins with improved inhibition of HIV entry in a live virus assay (IC 50 = 190−770 nM). 14 ■ RESULTS AND DISCUSSION Helix-Grafted Sac7d (Sac7d-Cpep) Potently Binds 5-Helix in E. coli Cell Lysate. Previous studies suggested a relationship between the size of the helix-grafted display scaffold and HIV-1 entry inhibition: smaller scaffolds are more effective.…”

mentioning

confidence: 99%

“…Our second-generation N-terminal helix-grafted protein (Cpep-ELMO) modestly inhibits HIV entry (IC 50 > 1 μM) in a live virus assay. More recently, we showed that yeast display optimization of grafted residues on Cpep-ELMO led to proteins with improved inhibition of HIV entry in a live virus assay (IC 50 = 190–770 nM) …”

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confidence: 99%

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Evolved Proteins Inhibit Entry of Enfuvirtide-Resistant HIV-1

et al. 2019

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Drugs that block HIV-1 entry are relatively limited. Enfuvirtide is a 36-residue synthetic peptide that targets gp41 and blocks viral fusion. However, Enfuvirtide-resistant HIV has been reported, and this peptide drug requires daily injection. Previously, we have reported helix-grafted display proteins, consisting of HIV-1 gp41 C-peptide helix grafted onto Pleckstrin Homology domains. Some of these biologics inhibit HIV-1 entry with relatively modest and varied potency (IC50 = 190 nM to >1 μM). Here, we report that gp41 C-peptide helix-grafted Sac7d (Sac7d-Cpep) potently suppresses HIV-1 entry in a live virus assay (IC50 = 1.9–12.4 nM). Yeast display sequence optimization of solvent exposed helix residues led to new biologics with improved expression in E. coli (a common biosimilar expression host), with no appreciable change in entry inhibition. Evolved proteins inhibit the entry of a clinically relevant mutant of HIV-1 that is gp41 C-peptide sensitive and Enfuvirtide resistant. Fusion proteins designed for serum stability also potently suppress HIV-1 entry. Collectively, we report several evolved biologics that are functional against an Enfuvirtide-resistant strain and are designed for serum stability.

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Antibody‐Recruitment as a Therapeutic Strategy: A Brief History and Recent Advances

et al. 2022

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Antibodies are a significant and growing sector within the global pharmaceutical industry. The popularity of antibodies as therapeutics derives from -at least in part -evolvable affinity for virtually any disease-relevant cell surface receptor, as well as unique immunotherapeutic mechanisms of action, including neutralization, antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC). While advances in the large-scale expression and purification of therapeutic antibodies have been made, these remain costly and laborious tasks. Agents that redirect endogenous antibodies to target a pathogen or malignant cell obviate the need for new antibody discovery and production. Chimeric antibody-recruiting technologies consist of a target cell surface receptor binding domain, and an endogenous antibody-binding domain. By design, these agents bring endogenous antibodies to the surface of a target pathogen or diseased cell, which can result in targeted cytotoxicity by antibody-dependent mechanisms. This review highlights seminal contributions and recent advances in this growing and important therapeutic field. Current Limitations to the Broader Use of Antibodies as TherapeuticsTheir evolvability, incredible in vivo stability, and diverse mechanisms of action make antibodies well suited for use as [a] Dr.

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Evaluation of sequence variability in HIV-1 gp41 C-peptide helix-grafted proteins

Cited by 3 publications

References 23 publications

Antiviral Peptides: Identification and Validation

Antiviral Peptides: Identification and Validation

Evolved Proteins Inhibit Entry of Enfuvirtide-Resistant HIV-1

Antibody‐Recruitment as a Therapeutic Strategy: A Brief History and Recent Advances

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