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Engineering a Higher Efficacy Anti-Heparan Sulfate Peptide for an Entry-Based Antiviral Therapy

機(jī)譯：工程設(shè)計(jì)一種更高功效的抗入門級(jí)抗病毒治療抗乙酰肝素硫酸鹽肽

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Primary and recurring herpes simplex virus-1 (HSV-1) infections can cause different pathologies in the eye and in severe cases it can result in permanent blindness. The current antiviral treatments for HSV-1 belong to a class of nucleoside analogs that inhibit viral DNA polymerase and block viral replication. Since they all target the same step in viral lifecycle, emergence of drug resistance is on the rise. Topical antivirals get eliminated through absorbance from ocular tissues or through the nasolacrimal duct resulting in lower bioavailability and frequent applications to reduce symptoms. These challenges need to be addressed by developing newer treatment options that target different stages in the viral lifecycle and by utilizing innovative technologies to enhance the efficacy and residence time of a drug on the cornea. Previous work from our lab discovered a unique arginine-rich peptide called G2. The peptide was specifically isolated against heparan sulfate (HS). HSV-1 used HS for attaching to cells and initiating entry. The G2 peptide binds to HS and inhibits viral entry and subsequent infection. Although peptides are fast growing as potential therapeutic molecules due to their high specificity, they are susceptible to protease degradation resulting in low activity and availability. The goal of this study is to increase the efficacy and/or stability of the G2 peptide that can either be used as a standalone preventive management or as a therapeutic in combination with existing antiviral treatments in controlling ocular herpes infection. Using peptide conjugation and peptide structure modification strategies and contact lenses as a drug delivery system, this study shows that the modified peptides are stable and significantly block viral entry and subsequent infection. The modified peptides are the first of its kind and may represent a new class of antiviral compounds. Additionally, other microorganisms such as fungi and bacteria also use HS for their pathogenesis. Thus, these efficacious forms of G2 may represent a broad-spectrum drug against these microbes.
機(jī)譯：原發(fā)性和復(fù)發(fā)性單純皰疹病毒1（HSV-1）感染可引起眼睛不同的病狀，嚴(yán)重時(shí)可導(dǎo)致永久性失明。目前，HSV-1的抗病毒治療屬于一類抑制病毒DNA聚合酶并阻斷病毒復(fù)制的核苷類似物。由于它們都靶向病毒生命周期中的同一步驟，因此耐藥性的出現(xiàn)正在上升。通過(guò)從眼組織吸收或通過(guò)鼻淚管吸收局部抗病毒藥物，導(dǎo)致較低的生物利用度并經(jīng)常使用以減輕癥狀。這些挑戰(zhàn)需要通過(guò)開(kāi)發(fā)針對(duì)病毒生命周期不同階段的更新治療方案以及利用創(chuàng)新技術(shù)來(lái)提高藥物在角膜上的功效和停留時(shí)間來(lái)解決。我們實(shí)驗(yàn)室以前的工作發(fā)現(xiàn)了一種獨(dú)特的富含精氨酸的肽G2。專門針對(duì)硫酸乙酰肝素（HS）分離了該肽。 HSV-1使用HS附著到細(xì)胞并啟動(dòng)進(jìn)入。 G2肽與HS結(jié)合并抑制病毒進(jìn)入和隨后的感染。盡管由于其高特異性，肽作為潛在的治療分子正在快速增長(zhǎng)，但它們易于被蛋白酶降解，從而導(dǎo)致活性和利用率低。這項(xiàng)研究的目的是提高G2肽的功效和/或穩(wěn)定性，該G2肽既可以用作獨(dú)立的預(yù)防措施，也可以與現(xiàn)有的抗病毒治療劑結(jié)合使用來(lái)控制眼皰疹感染。使用肽結(jié)合和肽結(jié)構(gòu)修飾策略以及隱形眼鏡作為藥物遞送系統(tǒng)，這項(xiàng)研究表明修飾的肽是穩(wěn)定的，并顯著阻止病毒進(jìn)入和隨后的感染。修飾的肽是第一種，可能代表一類新的抗病毒化合物。此外，其他微生物（例如真菌和細(xì)菌）也使用HS進(jìn)行發(fā)病。因此，這些有效形式的G2可能代表了針對(duì)這些微生物的廣譜藥物。

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  • 作者

    Jaishankar, Dinesh.;

  • 作者單位

    University of Illinois at Chicago.;

  • 授予單位 University of Illinois at Chicago.;
  • 學(xué)科 Biomedical engineering.;Virology.;Ophthalmology.
  • 學(xué)位 Ph.D.
  • 年度 2017
  • 頁(yè)碼 142 p.
  • 總頁(yè)數(shù) 142
  • 原文格式 PDF
  • 正文語(yǔ)種 eng
  • 中圖分類 遙感技術(shù);
  • 關(guān)鍵詞

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