Simplified θ-defensins

Search for new antivirals

Piotr Ruchala, Sylvia Cho, Amy L. Cole, Colleen Carpenter, Chun Ling Jung, Hai Luong, Ewa D. Micewicz, Alan J. Waring, Alexander M. Cole, Betsy Herold, Robert I. Lehrer

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major limitations to their clinical use hampered their development as potential antivirals, namely difficult multi-step synthesis for their production with low final yield of desired product (~5%), and unfavorable pharmacokinetics (rapid enzymatic degradation and/or renal clearance). Recently we designed and screened two sub-libraries of new peptide-based entry inhibitors mimicking the structure of humanized θ-defensins, designated as Hapivirins (HpVs) and Diprovirins (DpVs). Although the new peptides are smaller (13-residues) and structurally more simple than retrocyclins, several retained their ability to protect cells from infection by HIV-1 and HSV-2. The most active compound, DpV16, was chosen for a second round of modifications based on (1) its potent antiviral activity (2) its ease of synthesis, and (3) the low cost of production. Subsequently, we created a library of a second generation DpV-analogues with enhanced properties. Collectively, our findings to date suggest that simplified θ-defensins are suitable candidates for further modifications to obtain analogues with clinically favorable pharmacokinetics that may be produced in large quantities using a standard chemical approach. Considering their small size, they could be used either topically (topical microbicides) and/or for systemic applications (entry inhibitors).

Original languageEnglish (US)
Pages (from-to)325-336
Number of pages12
JournalInternational Journal of Peptide Research and Therapeutics
Volume17
Issue number4
DOIs
StatePublished - Dec 2011

Fingerprint

Defensins
Peptides
Antiviral Agents
Pharmacokinetics
Viral Interference
Peptide Library
Local Anti-Infective Agents
Human Herpesvirus 2
Immune system
Primates
Libraries
HIV-1
Immune System
Fusion reactions
Kidney
Costs and Cost Analysis
Degradation
Molecules
Infection
Costs

Keywords

  • Antivirals
  • Defensins
  • HIV-1
  • HSV-2
  • Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Bioengineering
  • Molecular Medicine
  • Drug Discovery
  • Analytical Chemistry

Cite this

Ruchala, P., Cho, S., Cole, A. L., Carpenter, C., Jung, C. L., Luong, H., ... Lehrer, R. I. (2011). Simplified θ-defensins: Search for new antivirals. International Journal of Peptide Research and Therapeutics, 17(4), 325-336. https://doi.org/10.1007/s10989-011-9272-x

Simplified θ-defensins : Search for new antivirals. / Ruchala, Piotr; Cho, Sylvia; Cole, Amy L.; Carpenter, Colleen; Jung, Chun Ling; Luong, Hai; Micewicz, Ewa D.; Waring, Alan J.; Cole, Alexander M.; Herold, Betsy; Lehrer, Robert I.

In: International Journal of Peptide Research and Therapeutics, Vol. 17, No. 4, 12.2011, p. 325-336.

Research output: Contribution to journalArticle

Ruchala, P, Cho, S, Cole, AL, Carpenter, C, Jung, CL, Luong, H, Micewicz, ED, Waring, AJ, Cole, AM, Herold, B & Lehrer, RI 2011, 'Simplified θ-defensins: Search for new antivirals', International Journal of Peptide Research and Therapeutics, vol. 17, no. 4, pp. 325-336. https://doi.org/10.1007/s10989-011-9272-x
Ruchala, Piotr ; Cho, Sylvia ; Cole, Amy L. ; Carpenter, Colleen ; Jung, Chun Ling ; Luong, Hai ; Micewicz, Ewa D. ; Waring, Alan J. ; Cole, Alexander M. ; Herold, Betsy ; Lehrer, Robert I. / Simplified θ-defensins : Search for new antivirals. In: International Journal of Peptide Research and Therapeutics. 2011 ; Vol. 17, No. 4. pp. 325-336.
@article{461faabef74d4784b6e89f629c78e927,
title = "Simplified θ-defensins: Search for new antivirals",
abstract = "Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major limitations to their clinical use hampered their development as potential antivirals, namely difficult multi-step synthesis for their production with low final yield of desired product (~5{\%}), and unfavorable pharmacokinetics (rapid enzymatic degradation and/or renal clearance). Recently we designed and screened two sub-libraries of new peptide-based entry inhibitors mimicking the structure of humanized θ-defensins, designated as Hapivirins (HpVs) and Diprovirins (DpVs). Although the new peptides are smaller (13-residues) and structurally more simple than retrocyclins, several retained their ability to protect cells from infection by HIV-1 and HSV-2. The most active compound, DpV16, was chosen for a second round of modifications based on (1) its potent antiviral activity (2) its ease of synthesis, and (3) the low cost of production. Subsequently, we created a library of a second generation DpV-analogues with enhanced properties. Collectively, our findings to date suggest that simplified θ-defensins are suitable candidates for further modifications to obtain analogues with clinically favorable pharmacokinetics that may be produced in large quantities using a standard chemical approach. Considering their small size, they could be used either topically (topical microbicides) and/or for systemic applications (entry inhibitors).",
keywords = "Antivirals, Defensins, HIV-1, HSV-2, Peptides",
author = "Piotr Ruchala and Sylvia Cho and Cole, {Amy L.} and Colleen Carpenter and Jung, {Chun Ling} and Hai Luong and Micewicz, {Ewa D.} and Waring, {Alan J.} and Cole, {Alexander M.} and Betsy Herold and Lehrer, {Robert I.}",
year = "2011",
month = "12",
doi = "10.1007/s10989-011-9272-x",
language = "English (US)",
volume = "17",
pages = "325--336",
journal = "International Journal of Peptide Research and Therapeutics",
issn = "1573-3149",
publisher = "Springer Netherlands",
number = "4",

}

TY - JOUR

T1 - Simplified θ-defensins

T2 - Search for new antivirals

AU - Ruchala, Piotr

AU - Cho, Sylvia

AU - Cole, Amy L.

AU - Carpenter, Colleen

AU - Jung, Chun Ling

AU - Luong, Hai

AU - Micewicz, Ewa D.

AU - Waring, Alan J.

AU - Cole, Alexander M.

AU - Herold, Betsy

AU - Lehrer, Robert I.

PY - 2011/12

Y1 - 2011/12

N2 - Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major limitations to their clinical use hampered their development as potential antivirals, namely difficult multi-step synthesis for their production with low final yield of desired product (~5%), and unfavorable pharmacokinetics (rapid enzymatic degradation and/or renal clearance). Recently we designed and screened two sub-libraries of new peptide-based entry inhibitors mimicking the structure of humanized θ-defensins, designated as Hapivirins (HpVs) and Diprovirins (DpVs). Although the new peptides are smaller (13-residues) and structurally more simple than retrocyclins, several retained their ability to protect cells from infection by HIV-1 and HSV-2. The most active compound, DpV16, was chosen for a second round of modifications based on (1) its potent antiviral activity (2) its ease of synthesis, and (3) the low cost of production. Subsequently, we created a library of a second generation DpV-analogues with enhanced properties. Collectively, our findings to date suggest that simplified θ-defensins are suitable candidates for further modifications to obtain analogues with clinically favorable pharmacokinetics that may be produced in large quantities using a standard chemical approach. Considering their small size, they could be used either topically (topical microbicides) and/or for systemic applications (entry inhibitors).

AB - Peptides of the innate immune system provide intriguing templates for designing novel antiviral molecules. θ-defensins are nonhuman primate peptides with broad-spectrum antiviral activities. The activity of these compounds is mediated through interference with viral fusion, and this activity is based upon key structural features. However, two major limitations to their clinical use hampered their development as potential antivirals, namely difficult multi-step synthesis for their production with low final yield of desired product (~5%), and unfavorable pharmacokinetics (rapid enzymatic degradation and/or renal clearance). Recently we designed and screened two sub-libraries of new peptide-based entry inhibitors mimicking the structure of humanized θ-defensins, designated as Hapivirins (HpVs) and Diprovirins (DpVs). Although the new peptides are smaller (13-residues) and structurally more simple than retrocyclins, several retained their ability to protect cells from infection by HIV-1 and HSV-2. The most active compound, DpV16, was chosen for a second round of modifications based on (1) its potent antiviral activity (2) its ease of synthesis, and (3) the low cost of production. Subsequently, we created a library of a second generation DpV-analogues with enhanced properties. Collectively, our findings to date suggest that simplified θ-defensins are suitable candidates for further modifications to obtain analogues with clinically favorable pharmacokinetics that may be produced in large quantities using a standard chemical approach. Considering their small size, they could be used either topically (topical microbicides) and/or for systemic applications (entry inhibitors).

KW - Antivirals

KW - Defensins

KW - HIV-1

KW - HSV-2

KW - Peptides

UR - http://www.scopus.com/inward/record.url?scp=81355146481&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81355146481&partnerID=8YFLogxK

U2 - 10.1007/s10989-011-9272-x

DO - 10.1007/s10989-011-9272-x

M3 - Article

VL - 17

SP - 325

EP - 336

JO - International Journal of Peptide Research and Therapeutics

JF - International Journal of Peptide Research and Therapeutics

SN - 1573-3149

IS - 4

ER -