Development of a Vaginal Fast-Dissolving Insert Combining Griffithsin and Carrageenan for Potential Use Against Sexually Transmitted Infections

Lal, Manjari; Lai, Manshun; Ugaonkar, Shweta R.; Wesenberg, Asa; Kizima, Larisa; Rodríguez, Aixa; Levendosky, Keith; Mizenina, Olga; Fernández-Romero, José A.; Zydowsky, Thomas M.

doi:10.1016/j.xphs.2018.06.002

Cited by 31 publications

(31 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most advanced freeze-dried vaginal insert in development for prevention of HIV and sexually transmitted infections (STI) is the Griffithsin (GRFT)/Carrageenan (CG) fast-dissolve insert from Population Council in collaboration with PATH [20,33]. GRFT is a naturally-occurring algae-derived protein that inhibits HIV and other pathogens, including herpes simplex virus (HSV-2); CG is a sulfated polysaccharide with potency against human papilloma virus (HPV).…”

Section: Fast Dissolving Insertsmentioning

confidence: 99%

“…The GRFT/CG fast-dissolve inserts disintegrated in <1 min in a physiologically relevant volume (∼1 mL) of vaginal fluid, transforming rapidly into a viscous, spreading gel with mucoadhesive properties [34]. In macaques, the GRFT/CG inserts demonstrated protection in a high dose vaginal SHIV challenge study 4 h after insert insertion, and in mice, the inserts protected against vaginal HSV-2 and HPV pseudo virus [33,35]. While clinical testing of the GRFT/CG insert has yet to be conducted, a Phase I study (NCT02875119) of a GRFT/CG gel formulation was completed in 2018, providing first-in-human safety, PK and PD data for GRFT dosed vaginally.…”

Section: Fast Dissolving Insertsmentioning

confidence: 99%

See 1 more Smart Citation

Topical Inserts: A Versatile Delivery Form for HIV Prevention

et al. 2019

View full text Add to dashboard Cite

The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.

show abstract

Section: Fast Dissolving Insertsmentioning

confidence: 99%

Section: Fast Dissolving Insertsmentioning

confidence: 99%

Topical Inserts: A Versatile Delivery Form for HIV Prevention

et al. 2019

View full text Add to dashboard Cite

show abstract

“…GRFT was resistant to digestion by eight different proteases including pepsin, papain, leucine aminopeptidase, pronase, α-chymotrypsin, proteinase K, endoproteinase, and trypsin [56]. A number of different nanoparticle drug delivery systems have been tested to provide sustained and controlled delivery of GRFT, improve its solubility, protect its payloads, and enhance its mucosal permeability (Table 9) [57,58,59,60]. PLGA (poly lactic-co-glycolic acid) nanoparticles with a diameter of approximately 180–200 nm were successfully used in the co-delivery of GRFT and dapivirine in vitro [60].…”

Section: A Formulation For Efficient Deliverymentioning

confidence: 99%

“…Grooms et al successfully generated GRFT-modified electrospun fibers to inactivate HIV prior to cellular entry [57]. Furthermore, Lal et al developed a self-administered, vaginal fast-dissolving insert (FDI) produced by freeze-drying that delivered safe and effective amounts of GRFT and carrageenan (GC), a sulfated polysaccharide extracted from seaweed [58]. Fibers comprised of methoxy polyethylene glycol-PLGA: poly n-butyl acrylate-co-acrylic acid (mPEG-PLGA: PBA-co-PAA) were able to achieve high GRFT loading.…”

Section: A Formulation For Efficient Deliverymentioning

confidence: 99%

Griffithsin, a Highly Potent Broad-Spectrum Antiviral Lectin from Red Algae: From Discovery to Clinical Application

Lee

2019

Marine Drugs

103

View full text Add to dashboard Cite

Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host’s immune system and as a preventive and therapeutic antiviral strategy. Recently, several plant-derived carbohydrate-binding proteins (lectins) have emerged as a new class of antiviral biologics by taking advantage of a unique glycosylation pattern only found on the surface of viruses. In particular, a red algae-derived griffithsin (GRFT) protein has demonstrated superior in vitro and in vivo antiviral activity with minimum host toxicity against a variety of clinically relevant, enveloped viruses. This review examines the structural characteristics of GRFT, focusing on its carbohydrate-binding capability. Its in vitro antiviral profiles against human immunodeficiency virus (HIV) are also discussed followed by a description of the results from a combination study using anti-HIV drugs. The results of several studies regarding its novel antiviral mechanism of action are provided in conjunction with an explanation of viral resistance profiles to GRFT. In addition, its in vitro and in vivo host toxicity profiles are summarized with its pharmacokinetic behavior using in vivo efficacy study results. Also, a large-scale production and formulation strategy, as well as a drug delivery strategy, for GRFT as a new class of broad-spectrum microbicides is discussed. Finally, results from two ongoing clinical studies examining GRFT’s effects on viruses are presented.

show abstract

“…leaves (28)(29)(30)(31), Escherichia coli (32), and rice endosperm (33) and has been shown to have low or no toxicity, an unfolding temperature of 78.8°C, stability at pH 4 to 8, resistance to proteolytic degradation, conservation of potency after incubation at temperatures of up to 50°C, and safety in mice and macaques when applied topically, injected, or ingested (7,25,28,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Multiple groups have begun in-human trials (44,45).…”

mentioning

confidence: 99%

Griffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126

Fischer

Nguyen

LiWang

2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Griffithsin (Grft) is an antiviral lectin that has been shown to potently inhibit HIV-1 by binding high-mannose N-linked glycosylation sites on HIV-1 gp120. A key factor for Grft potency is glycosylation at N295 of gp120, which is directly adjacent to N332, a target glycan for an entire class of broadly neutralizing antibodies (bNAbs). Here, we unify previous work on the importance of other glycans to Grft potency against HIV-1 and Grft’s role in mediating the conformational change of gp120 by mutating nearly every glycosylation site in gp120. In addition to a significant loss of Grft activity by the removal of glycosylation at N295, glycan absence at N332 or N448 was found to have moderate effects on Grft potency. Interestingly, in the absence of N295, Grft effectiveness could be improved by a mutation that results in the glycan at N448 shifting to N446, indicating that the importance of individual glycans may be related to their effect on glycosylation density. Grft’s ability to alter the structure of gp120, exposing the CD4 binding site, correlated with the presence of glycosylation at N295 only in clade B strains, not clade C strains. We further demonstrate that Grft can rescue the activity of the bNAbs PGT121 and PGT126 in the event of a loss or a shift of glycosylation at N332, where the bNAbs suffer a drastic loss of potency. Despite targeting the same region, Grft in combination with PGT121 and PGT126 produced additive effects. This indicates that Grft could be an important combinational therapeutic.

show abstract

Development of a Vaginal Fast-Dissolving Insert Combining Griffithsin and Carrageenan for Potential Use Against Sexually Transmitted Infections

Cited by 31 publications

References 53 publications

Topical Inserts: A Versatile Delivery Form for HIV Prevention

Topical Inserts: A Versatile Delivery Form for HIV Prevention

Griffithsin, a Highly Potent Broad-Spectrum Antiviral Lectin from Red Algae: From Discovery to Clinical Application

Griffithsin Retains Anti-HIV-1 Potency with Changes in gp120 Glycosylation and Complements Broadly Neutralizing Antibodies PGT121 and PGT126

Contact Info

Product

Resources

About