Human α-defensins block papillomavirus infection

Buck, Christopher B.; Day, Patricia M.; Thompson, Cynthia D.; Łubkowski, J.; Lu, Wuyuan; Lowy, Douglas R.; Schiller, John T.

doi:10.1073/pnas.0508033103

Cited by 213 publications

(187 citation statements)

References 67 publications

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“…In recent studies, HNPs 1-3 and HD5 proved to be potent antagonists of infection by human papillomaviruses, the primary causes of cervical cancer (36). HD5 was particularly active against sexually transmitted papillomaviruses, with IC 50 values in the high nanogram per milliliter range.…”

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confidence: 99%

“…HD5 was particularly active against sexually transmitted papillomaviruses, with IC 50 values in the high nanogram per milliliter range. HD5 did not block virion binding or internalization, instead acting by preventing the escape of virions from their endocytic vesicles (36). HD5 inhibits adenovirus infections by binding to the virus capsid and preventing its subsequent uncoating, an event the virus requires to escape the endosomal compartment and enter the cytosol (37).…”

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confidence: 99%

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Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

Lehrer

Jung

Ruchala

et al. 2009

The Journal of Immunology

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Four of the six human α-defensins (human neutrophil peptides 1–3 and human α-defensin 5; HD5) have a lectin-like ability to bind glycosylated proteins. Using HD5 as a model, we applied surface plasmon resonance techniques to gain insights into this property. HD5 bound natural glycoproteins > neoglycoproteins based on BSA > nonglycosylated BSA ≫ free sugars. The affinity of HD5 for simple sugars covalently bound to BSA was orders of magnitude greater than its affinity for the same sugars in solution. The affinity of HD5 for protein-bound carbohydrates resulted from multivalent interactions which may also involve noncarbohydrate residues of the proteins. HD5 showed concentration-dependent self-association that began at submicromolar concentrations and proceeded to dimer and tetramer formation at concentrations below 5 μM. The (R9A, R28A) and (R13A, R32A) analogs of HD5 showed greatly reduced self-association as well as minimal binding to BSA and to BSA-affixed sugars. From this and other evidence, we conclude that the extensive binding of HD5 to (neo)glycoproteins results from multivalent nonspecific interactions of individual HD5 molecules with carbohydrate and noncarbohydrate moieties of the target molecule and that the primary binding events are magnified and enhanced by subsequent in situ assembly and oligomerization of HD5. Self-association and multivalent binding may play integral roles in the ability of HD5 to protect against infections caused by viruses and other infectious agents.

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Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

Lehrer

Jung

Ruchala

et al. 2009

The Journal of Immunology

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“…Adenovirus infection is neutralized by blocking viral uncoating and subsequent release of the genome (29)(30)(31). Alpha defensins have also been shown to block papillomavirus infection by sequestering the virions in their en-docytic vesicles (32). The human alpha defensin HD5 inhibits replication of the JCPyV-related polyomavirus BK by blocking binding to host cells (33).…”

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The Human Alpha Defensin HD5 Neutralizes JC Polyomavirus Infection by Reducing Endoplasmic Reticulum Traffic and Stabilizing the Viral Capsid

Zins

Nelson

Maginnis

et al. 2014

J Virol

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“…Yet cationicity alone does not explain the strain selectivity of different defensins. Furthermore, unlike human ␣-defensins and (perhaps) HBD3, the more positively charged ␤-defensins are not lectins and do not inhibit bacterial toxins and many viruses (31)(32)(33)(34)(35)(36).…”

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Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1

Wei

Pazgier

Leeuw

et al. 2010

Journal of Biological Chemistry

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We performed a comprehensive alanine scan of human ␣-defensin HNP1 and tested the ability of the resulting analogs to kill Staphylococcus aureus, inhibit anthrax lethal factor, and bind human immunodeficiency virus-1 gp120. By far, the most deleterious mutation for all of these functions was W26A. The activities lost by W26A-HNP1 were restored progressively by replacing W26 with non-coded, straight-chain aliphatic amino acids of increasing chain length. The hydrophobicity of residue 26 also correlated with the ability of the analogs to bind immobilized wild type HNP1 and to undergo further self-association. Thus, the hydrophobicity of residue 26 is not only a key determinant of the direct interactions of HNP1 with target molecules, but it also governs the ability of this peptide to form dimers and more complex quaternary structures at micromolar concentrations. Although all defensin peptides are cationic, their amphipathicity is at least as important as their positive charge in enabling them to participate in innate host defense.

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Human α-defensins block papillomavirus infection

Abstract: cathelicidin ͉ hCAP18 ͉ lactoferrin ͉ LL-37 ͉ microbicide

Cited by 213 publications

References 67 publications

Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

Multivalent Binding of Carbohydrates by the Human α-Defensin, HD5

The Human Alpha Defensin HD5 Neutralizes JC Polyomavirus Infection by Reducing Endoplasmic Reticulum Traffic and Stabilizing the Viral Capsid

Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1

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