Development of peptide inhibitors of HIV transmission

Shi, Siyu; Nguyen, Peter K.; Cabral, Henry J.; Diez-Barroso, Ramon; Derry, Paul J.; Kanahara, Satoko M.; Kumar, Vivek

doi:10.1016/j.bioactmat.2016.09.004

Cited by 24 publications

(16 citation statements)

References 252 publications

(300 reference statements)

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“…Most inhibit viral enzymes, and a limited number of drugs inhibit cell surface binding, internalization, viral-cell membrane fusion, or virus uncoating (e.g., refs. [30][31][32][33]. Our results validate intracellular virus trafficking as a therapeutic vulnerability.…”

Section: Fluorescence Intensitysupporting

confidence: 69%

Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry

Zhang

Moreno

Lambert

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Virus replication requires critical interactions between viral proteins and cellular proteins that mediate many aspects of infection, including the transport of viral genomes to the site of replication. In human papillomavirus (HPV) infection, the cellular protein complex known as retromer binds to the L2 capsid protein and sorts incoming virions into the retrograde transport pathway for trafficking to the nucleus. Here, we show that short synthetic peptides containing the HPV16 L2 retromer-binding site and a cell-penetrating sequence enter cells, sequester retromer from the incoming HPV pseudovirus, and inhibit HPV exit from the endosome, resulting in loss of viral components from cells and in a profound, dose-dependent block to infection. The peptide also inhibits cervicovaginal HPV16 pseudovirus infection in a mouse model. These results confirm the retromer-mediated model of retrograde HPV entry and validate intracellular virus trafficking as an antiviral target. More generally, inhibiting virus replication with agents that can enter cells and disrupt essential protein-protein interactions may be applicable in broad outline to many viruses.

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Section: Fluorescence Intensitysupporting

confidence: 69%

Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry

Zhang

Moreno

Lambert

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Such dataset of 130 peptides is further utilized while training GAN. The peptides taken from literature and clinical trials are listed in following references - HIV candidates (Liang et al , 2020; Shi et al , 2016; Chupradit et al , 2017; Coffey et al , 1997); SARS COV (Xia et al , 2020); MERS (Zhao et al , 2016);T20 (Ding et al , 2017);Hepatitis B (Lempp et al , 2016);…”

Section: Methodsmentioning

confidence: 99%

PandoraGAN: Generating antiviral peptides using Generative Adversarial Network

Surana

Arora

Singh

et al. 2021

Preprint

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The continuous increase in pathogenic viruses and the intensive laboratory research for development of novel antiviral therapies often poses challenge in terms of cost and time efficient drug design. This accelerates research for alternate drug candidates and contributes to recent rise in research of antiviral peptides against many of the viruses. With limited information regarding these peptides and their activity, modifying the existing peptide backbone or developing a novel peptide is very time consuming and a tedious process. Advanced deep learning approaches such as generative adversarial networks (GAN) can be helpful for wet lab scientist to screen potential antiviral candidates of interest and expedite the initial stage of peptide drug development. To our knowledge this is the first ever use of GAN models for antiviral peptides across the viral spectrum. In this study, we develop PandoraGAN that utilizes GAN to design bio active antiviral peptides. Available antiviral peptide data was manually curated for preparing highly active peptides data set to include peptides with lower IC50 values. We further validated the generated sequences comparing the physico-chemical properties of generated antiviral peptides with manually curated highly active training data. Antiviral sequences generated by PandoraGAN are available on PandoraGAN server.

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“…It binds to the hydrophobic pocket of the CCR5 co-receptor and changes its conformation, and interrupts the binding of the V3 loop of the viral membrane protein gp120 to CCR5, in order to prevent viral entry into the host cell [ 29 ]. Although this drug targets the co-receptor of the host cell, it has been reported to acquire resistance using a different resistance mechanism, unlike other anti-HIV drugs that directly bind to the viral protein [ 30 31 ]. The mechanisms of resistance acquisition for this drug include a change of the infection route to CXCR4 instead of CCR5 of the viral protein gp120, a strengthening of coherence with CCR5 stronger than maraviroc, and the acquisition of penetration ability by recognizing the maraviroc-CCR5 complex [ 10 32 33 ].…”

Section: Ccr5 Antagonistsmentioning

confidence: 99%

An Overview of Human Immunodeficiency Virus-1 Antiretroviral Drugs: General Principles and Current Status

2021

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Treatment with highly active antiretroviral therapy (HAART) can prolong a patient's life-span by disrupting pivotal steps in the replication cycle of the human immunodeficiency virus-1 (HIV-1). However, drug resistance is emerging as a major problem worldwide due to the prolonged period of treatment undergone by HIV-1 patients. Since the approval of zidovudine in 1987, over thirty antiretroviral drugs have been categorized into the following six distinct classes based on their biological function and resistance profiles: (1) nucleoside analog reverse-transcriptase inhibitors; (2) non–nucleoside reverse transcriptase inhibitors; (3) integrase strand transferase inhibitors; (4) protease inhibitors; (5) fusion inhibitors; and (6) co-receptor antagonists. Additionally, several antiretroviral drugs have been developed recently, such as a long active drug, humanized antibody and pro-drug metabolized into an active form in the patient's body. Although plenty of antiretroviral drugs are beneficially used to treat patients with HIV-1, the ongoing efforts to develop antiretroviral drugs have overcome the drug resistances, adverse effects, and limited adherence of drugs observed in previous drugs to some extent. Furthermore, studies focused on agents targeting latent HIV-1 reservoirs should be strengthened, as that may lead to eradication of HIV-1.

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Development of peptide inhibitors of HIV transmission

Cited by 24 publications

References 252 publications

Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry

Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry

PandoraGAN: Generating antiviral peptides using Generative Adversarial Network

An Overview of Human Immunodeficiency Virus-1 Antiretroviral Drugs: General Principles and Current Status

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