Zinc inhibition of renin and the protease from human immunodeficiency virus type 1

Zhang, Zhong Yin; Reardon, Ilene M.; Hui, John O.; O'Connell, Kathy L.; Poorman, Roger A.; Tomasselli, Alfredo G.; Heinrikson, Robert L.

doi:10.1021/bi00100a001

Cited by 64 publications

(34 citation statements)

References 25 publications

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“…Several papers have discussed the benefit of zinc as a broadspectrum antimicrobial agent (4,19,20,27,29,42,45,54). However, there are characteristics of zinc salts that render zinc assessment problematic in a number of in vitro assays.…”

Section: Figmentioning

confidence: 99%

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Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

Fernández-Romero

Abraham

Rodríguez

et al. 2012

Antimicrob Agents Chemother

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Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard has in vitro activity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival; P < 0.001) against high-dose (10 6 -PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicity in vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosae in vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.

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Section: Figmentioning

confidence: 99%

“…Studies have shown that zinc salts have antiviral activity against a broad range of viruses, including HIV and HSV (4,7,19,20,27,29,45,54). Thus, topical application of formulations containing low-dose zinc salts represents a novel strategy for preventing the sexual transmission of HSV-2 and potentially HIV without the use of antiretroviral drugs.…”

mentioning

confidence: 99%

Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

Fernández-Romero

Abraham

Rodríguez

et al. 2012

Antimicrob Agents Chemother

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“…Inhibition of elastase activity by Zn 2+ ions was unexpected. Inhibition of activity by Zn 2+ has been observed with rennin and HIV-associated protease, as well as coagulation factor VIIa proteolytic activity (Pedersen et al 1991, Zhang et al 1991. Separation on SDS-PAGE showed the presence of 6 polypeptides in the purified material.…”

Section: Discussionmentioning

confidence: 94%

Identification and partial characterization of an elastolytic protease in the amphibian pathogen Batrachochytrium dendrobatidis

Moss¹,

Carty²,

Francisco³

2009

Dis. Aquat. Org.

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Batrachochytrium dendrobatidis (Bd) is a fungus that causes chytridiomycosis, a disease that has been implicated as a cause of amphibian population declines worldwide. Infected animals experience hyperkeratosis and sloughing of the epidermis due to penetration of the keratinized tissues by the fungus. These symptoms have led us to postulate that Bd produces proteases that play a role in the infection process. Here, we show that Bd is capable of degrading elastin in vitro, a protein found in the extracellular matrix of the host animal. Elastolytic enzyme activity was partially purified using ion exchange chromatography and size-exclusion filtration from cultures grown in inducing media. The elastolytic activity of the purified fraction had a pH optimum of 8, was strongly inhibited by EDTA and phenylmethylsulfonyl fluoride (PMSF), and was partially inhibited by an elastasespecific inhibitor. This activity was also enhanced by the presence of Mg 2+ and Ca 2+ but not Zn 2+. An antiserum directed against Aspergillus fumigatus serine protease (Alp) was found to react with a polypeptide of approximately 110 kDa from the purified material. Using immunofluorescence, this antiserum was also observed to react with zoospores and sporangia grown on toad skin. These observations suggest that Bd may produce proteases similar to those produced by other pathogenic fungi that are capable of degrading proteins found in the extracellular matrix. The proteolytic activity exhibited in vitro might aid the organism in its ability to colonize and destroy the epidermis of its amphibian host.

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“…Zinc stimulates water and electrolytes absorption from the intestinal mucosa and it increases the concentration of enterocyte brush-border enzymes [82]; it also exerts anti-inflammatory activities, through the inhibition of the NF-κB pathway and may inhibit TNF-α-induced cell death [83]. The HIV protease enzyme, which is essential for the production of new viral particles, can be inhibited by high zinc concentration [84]. In addition, zinc cellular levels affect HIV integration into the host genome.…”

Section: Zincmentioning

confidence: 99%

Micronutrients in HIV Infection Without HAART

Pinzone

Cacopardo

Nunnari

2015

Health of HIV Infected People

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Zinc inhibition of renin and the protease from human immunodeficiency virus type 1

Cited by 64 publications

References 25 publications

Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

Zinc Acetate/Carrageenan Gels Exhibit Potent Activity In Vivo against High-Dose Herpes Simplex Virus 2 Vaginal and Rectal Challenge

Identification and partial characterization of an elastolytic protease in the amphibian pathogen Batrachochytrium dendrobatidis

Micronutrients in HIV Infection Without HAART

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