Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: http://www.tandfonline.com/loi/ijdt20

Utility of Boron in Dermatology

David G. Jackson, Leah A. Cardwell, Elias Oussedik & Steven R. Feldman

To cite this article: David G. Jackson, Leah A. Cardwell, Elias Oussedik & Steven R.
Feldman (2017): Utility of Boron in Dermatology, Journal of Dermatological Treatment, DOI:
10.1080/09546634.2017.1363850

To link to this article: http://dx.doi.org/10.1080/09546634.2017.1363850

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 Utility of Boron in Dermatology

David G. Jackson1, PhD, Leah A. Cardwell 1, MD, Elias Oussedik, BS; Steven R. Feldman1,2,3,

MD, PhD

1
Center for Dermatology Research, Department of Dermatology, Wake Forest School of

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Medicine, Winston-Salem, North Carolina
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2
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina

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3
Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem,

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North Carolina
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Address correspondence to:
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Leah A. Cardwell, MD

Department of Dermatology, Wake Forest School of Medicine

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Medical Center Boulevard

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Winston-Salem, NC 27157-1071
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Phone: 313-790-5469, Fax: 336-716-7732, E-mail: lcardwell06@gmail.com

Funding source: none

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No human subjects were used in this study and the study was deemed exempt from IRB approval

by Wake Forest School of Medicine.

Keywords: atopic dermatitis, psoriasis, treatment, anti-inflammatory, antifungal

 Word Count: 1707, References: 46, Tables: 0, Figures: 3

Conflict of Interest: Dr. Feldman is a speaker for Janssen and Novartis. Dr. Feldman has received

grants from Galderma Laboratories, L.P., Janssen, Abbvie, Amgen, Stiefel/GlaxoSmithKline,

Celgene and Anacor. He is a consultant for Amgen, Baxter, Caremark, Gerson Lehrman Group,

Guidepoint Global, Hanall Pharmaceutical Co Ltd, Lilly, Merck, Mylan, Novartis, Pfizer,

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Qurient, Suncare Research and Xenoport. Dr. Feldman is the founder and holds stock in Causa

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Research and holds stock and is majority owner in Medical Quality Enhancement Corporation

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and the www.DrScore.com doctor rating/patient satisfaction website. He receives Royalties

from UpToDate and Xlibris. Dr. Cardwell and Dr. Jackson have no conflicts to disclose.
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 ABSTRACT

Introduction: Boron compounds are being investigated as therapies for dermatologic conditions.

Several features of boron chemistry make this element an ideal component in dermatologic

treatments. We review the published dermatologically-relevant clinical trials and case studies

pertaining to boron compounds.

Methods: PubMed was utilized to query terms boron, chemistry, drug, development,

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dermatology, atopic dermatitis, psoriasis, onychomycosis, tavaborole, AN 2690, crisaborole, and
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AN 2728. Clinical trials, case studies, animal studies and in vitro studies. pertaining to atopic

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dermatitis, psoriasis and onychomycosis were included.

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Results: Crisaborole 2% topical solution reduced atopic dermatitis lesions by approximately
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60% when compared to pre-treatment baseline. Crisaborole maintains its dose-dependent effect

in treatment of psoriasis and significantly reduces psoriatic plaques when compared to controls.
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Adverse effects were mild, frequency of events varied between studies. Crisaborole was well

tolerated when applied to sensitive skin. Topical tavaborole significantly reduced or eliminated
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onychomycosis with minimal side effects compared to placebo. Tavaborole was effective in
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treating recalcitrant onychomycosis.

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Discussion: Boron-based compounds form stable interactions with enzyme targets and are safe

medications for the treatment of atopic dermatitis, psoriasis, and onychomycosis. The mild and
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rare side effects of topical boron-based compounds may make them ideal treatments for

individuals with sensitive skin and pediatric populations.

 INTRODUCTION

Boron Chemistry and Drug Design

Boron is an essential nutrient with a variety of beneficial roles, including promotion of

wound healing, bone growth, and boosting antioxidant enzymes.1 Unique properties of boron

make it a promising new element in drug design.2 Boron-containing compounds are

approximately the same size as carbon-containing compounds, their small size allows them to

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occupy the active sites of various enzyme targets. Carbon hydrides are compounds which
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contain carbon and hydrogen forming chains and rings. Boron hydrides, the boron-based

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equivalent of carbon hydrides, form cages and clusters. The unique structure of boron hydrides

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provide flexibility, enabling them to occupy an enzymes active site with more ease than rigid
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carbon compounds.2 Boron is electron-deficient, its outer shell carries three electrons though it

has the capacity to hold four pairs of electrons. This characteristic of electron deficiency makes
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the atom a strong electrophile. Boron bonds with nucleophiles, allowing its electrons to

reorganize and create an anionic, tetrahedral structure.4

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Boron-based compounds can be used as enzyme inhibitors since boron and carbon atoms
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have similar sizes and structures.3 Like similar carbon-based ligands, boron-based compounds
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are able to enter an enzymes active site. The resulting bonding can be stronger than the

hydrophobic interactions that many other drugs use to inhibit protein targets, giving boron-based
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compounds good potential for pharmaceutical development .4 Unlike suicide inhibitors, which

irreversibly form covalent bonds with their targets, the bonds between boron-based inhibitors

and their protein targets are reversible. 4 The charge distribution of boron-containing compounds,

alteration in geometry upon binding to nucleophiles, and hydrophobic nature of these compounds

allows them to inhibit a wide spectrum of protein targets.2,4

 The acid dissociation constant (pKa) of boron can be modified by changing the composition

of the compound.5 By altering the pKa of boron during the laboratory-phase of drug

development, the affinity of a compound for an enzymes active site can be optimized.5

Pathogens that resist carbon-based treatments, such as penicillin-resistant bacteria, may be

susceptible to boron-based antibiotics that target various proteins.

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Clinical Application of Boron-based Medications
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Boron-containing compounds have achieved growing popularity in the healthcare field.

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Bortezomib, a modified dipeptidyl boronic acid that reversibly inhibits the 26S proteasome, has

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utility in preventing kidney transplant rejection, treating light-chain deposition disease and
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multiple myeloma.610 Inhibition of plasma cell 26S proteasome prevents degradation of the

inhibitory kappa beta protein (IB).10 Mitochondrial membrane potential is lost, which leads to
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activation of the intrinsic pathway of apoptosis. Plasma cell apoptosis prevents the development

of cancerous cell lineages in multiple myeloma and prevents secretion of antibodies in light
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chain deposition disease.6,9

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Crisaborole, a boron-containing topical phosphodiesterase 4 (PDE4) inhibitor, is a treatment

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option for atopic dermatitis and psoriasis.1115 Crisaborole was first discovered in an in vitro trial

of multiple boron-containing compounds against potential second messenger-producing enzyme

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targets related to atopic dermatitis and psoriasis.16 Inhibition of PDE4 blocks the conversion of

cyclic adenosine monophosphate (cAMP) to 5-AMP, preventing the release of pro-

inflammatory cytokines such as IFN-, TNF-, IL-2, and IL-5.11,1618 The binding of crisaborole

to PDE4 occurs at the bimetal center of the enzyme through a two-part mechanism. Crisaborole

binds to the adenine pocket, the boron component assumes a tetrahedral conformation and takes
 the place of the phosphate cAMP.19 This two-part mechanism resembles the binding of the

endogenous compound cAMP to PDE4.

Tavaborole, a boron-based fungal cytoplasmic leucyl-transfer RNA synthetase inhibitor,

has activity against multiple fungi including Trichophyton rubrum, a major cause of

onychomycosis.20,21 Inhibition of leucyl-transfer RNA synthetase prevents fungal protein

synthesis. Inhibition of this critical enzyme which had not been previously targeted by other

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antifungals may have utility in treating fungal infections. Since treatment of onychomycosis
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typically requires a lengthy regimen lasting weeks to months, a more cost-effective option such

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as simpler boron-based antifungals may be ideal.2

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Aminoacyl-tRNA synthetases facilitate protein synthesis by catalyzing the attachment of
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the proper amino acid to the tRNA. Certain aminoacyl-tRNA synthetases, such as leucyl-tRNA

synthetase, have editing sites which provide proofreading capability and assurance of correct
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amino acid attachment. Tavaborole, a boron-based therapy for onychomycosis inhibits the fungal

leucyl tRNA-synthetase thereby preventing synthesis of leucyl-tRNA and proteins.22 The boron
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atom in the oxaborole ring of tavaborole is vital to this mechanism of leucyl-tRNA synthetase
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inhibition. Tavaborole forms an adduct with leucyl-tRNA in the editing site of the leucyl tRNA
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synthetase enzyme, occupying the amino acid binding pocket in the editing site. The trapping of

this adduct in the editing site of leucyl-tRNA synthetase facilitates inhibition of the enzyme.
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Tavaboroles noncompetitive inhibition of aminoacyl-tRNA synthetase via the editing

site establishes the editing site as an ideal therapeutic target.22 The boron and oxaborole ring of

this compound are essential for enzyme inhibition.

Boron-containing compounds have emerged as promising agents in dermatology. Here,

we review the utility and efficacy of boron-based medications in dermatologic disease.

 METHODS

PubMed was utilized to query the key terms boron, chemistry, drug, development,

dermatology, atopic dermatitis, onychomycosis, tavaborole, AN 2690, crisaborole, AN 2728, and

psoriasis. The search results were categorized as clinical studies, case studies, animal studies and

in vitro studies.

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RESULTS
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Clinical Studies of Crisaborole and Tavaborole

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Crisaborole reduced the severity of atopic dermatitis lesions by a range of 54% to 71%

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when compared to control groups.13 (Table 1) Crisaborole has a dose-dependent effect on atopic
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dermatitis as crisaborole 2% ointment was more efficacious than crisaborole 0.5% ointment and

twice-daily dosing was more efficacious than once-daily dosing.13 Crisaborole 2% ointment
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administered twice-daily was the most effective crisaborole regimen for atopic dermatitis. Age,

race and gender did not influence its efficacy.23,24 Patients treated with crisaborole ointment
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typically had marked reduction in rash severity and pruritus.25,26 In one study, over 50% of
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patients reported near total or total clearance of lesions.26 The adverse effects of topical
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crisaborole were typically mild, including pain, pruritus and erythema at the application site.23,25
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Crisaborole ointment was well-tolerated, even when applied to sensitive areas such as the face,
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genitals, and intertriginous areas of healthy volunteers.27

Crisaborole maintains its dose-dependent effect in treatment of psoriasis and significantly

reduces psoriatic plaques when compared to controls.14,15 Crisaborole 5% ointment is effective

without increasing irritation in psoriasis patients.15

 Total clearance of fungus in tavaborole-treated toenails was achieved within 28 days,

and clear nail growth was maintained up to 4 months after treatment.28 (Table 2) Tavaborole

doses greater than 2.5% led to more clearance of onychomycosis compared to controls.29

Adverse effects of tavaborole are typically mild and include erythema, dermatitis, and exfoliation

localized to the application site.30 A case of efinaconazole-resistant Paecilomyces lilacinus

onychomycosis was resolved with tavaborole.31

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Animal and In Vitro Studies of Crisaborole and Tavaborole

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Crisaborole inhibited multiple second messenger-producing phosphodiesterases including

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PDE4, PDE7A1, PDE3Cat, and PDE1A in vitro at micromolar or submicromolar
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concentrations.16,19(Table 3). In a study on mouse ears rendered edematous by treatment with

phorbol ester, topical crisaborole reduced edema by 78%.16 Dexamethasone reduced edema to a
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similar extent. Crisaborole had a dose-dependent inhibitory effect on inflammatory cytokine

release from human blood mononuclear cells.32 Crisaborole had no genotoxic or mutagenic
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effects on bacteria, human cells, or rats.33

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Tavaborole possesses antifungal activity against Candida albicans and Trichophyton

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rubrum.3 It penetrates to a greater extent and maintains higher concentrations in ex vivo cadaver

fingernails than other antifungals such as terbinafine and cyclopirox.28,34 A long-term animal
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study to assess for drug carcinogenicity showed no carcinogenic effect of tavaborole in rat

models.35 Tavaborole is not genotoxic, even at doses 89 times the maximum dose for humans.33
 DISCUSSION

Favorable attributes of boron chemistry

Boron-based compounds are a new class of compounds for treatment of dermatological

diseases. Since boron is similar in size and structure to carbon, it can easily enter an enzymes

active site and inhibit the target protein. Their ability to form more flexible structures allows

them increased access to enzyme binding sites when compared to carbon-based compounds.2

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Boron-based compounds can form non-covalent or covalent bonds with their targets.36

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Covalently-modified human proteins are troublesome because these proteins might not be

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recognized as self and can trigger an autoimmune response.2 Drug-induced autoimmunity is

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counterproductive in the treatment of atopic dermatitis or psoriasis, so boron-based compounds
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designed to treat these conditions should exert their activity via non-covalent enzyme inhibition.

Crisaborole uses a novel mechanism to inhibit PDE4, this mechanism mimics the binding of
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cAMP to a target enzyme.19 This unique two-part mechanism of phosphodiesterase inhibition

may be a potential new area of research when designing anti-inflammatory drugs. The skin
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penetration and anti-inflammatory effect of crisaborole is comparable to that of steroids without

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the burden of side effects.

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Tavaboroles inhibition of aminoacyl-tRNA synthetase via the editing site establishes

the editing site as an ideal and unique therapeutic target. The targets of boron-based therapies in
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onychomycosis are fungal proteins rather than human proteins, so autoimmunity is not a

concern.
 Successful application of boron-based medicines in dermatology

Boron-containing compounds can be used to treat multiple dermatologic diseases.

Crisaborole reduces the extent of atopic dermatitis and psoriasis lesions with minimal side

effects.14,16,26 Tavaborole is efficacious in the treatment of onychomycosis. Topical

corticosteroids, a common treatment for psoriasis and atopic dermatitis, are associated with skin

atrophy, telangiectasias, tachyphylaxis, and HPA axis suppression when applied to large areas of

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the body.3739 Since atopic dermatitis commonly manifests in childhood, the milder side-effect

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profile of crisaborole may prove more favorable in this population.

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Terbinafine is commonly used in onychomycosis management, but it causes acute liver

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damage as a rare and dangerous side effect.40 Terbinafine inhibits CYP450 enzymes, thereby
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affecting the pharmacokinetics of other CYP450-metabolized drugs and increasing the likelihood

of drug-drug interactions.41,42 Since terbinafine is metabolized by liver enzymes, it is not ideal

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for patients with onychomycosis and comorbid liver disease. Tavaborole may be a better option

for these individuals.29,34,43 The biochemistry of boron-based medications such as tavaborole and
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crisaborole has taught us that diversifying the targets of dermatologic therapies is beneficial in
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expanding our treatment options.

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The side effect profiles associated with common treatments for atopic dermatitis,

psoriasis and onychomycoses range from mild to extreme. Advances in medicine and
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pharmacotherapy has led to the development of medications which avoid these potentially

dangerous side effects. Patients are complex and require a fine-tuned treatment regimen that

considers patient comorbidities, preference and prior treatments. Crisaborole and tavaborole are

novel drugs which will expand our armamentarium for atopic dermatitis, psoriasis and

onychomycosis.
 References

1. Pizzorno L. Nothing Boring About Boron. Integr Med (Encinitas). 2015;14(4):35-48.

http://www.ncbi.nlm.nih.gov/pubmed/26770156%5Cnhttp://www.pubmedcentral.nih.gov/

articlerender.fcgi?artid=PMC4712861.

2. Hunter P. Not boring at all. Boron is the new carbon in the quest for novel drug

candidates. EMBO Rep. 2009;10(2):125-128. doi:10.1038/embor.2009.2.

t
ip
3. Yang W, Gao X, Wang B. Boronic acid compounds as potential pharmaceutical agents.
Downloaded by [Australian Catholic University] at 03:11 13 August 2017

Med Res Rev. 2003;23(3):346-368. doi:10.1002/med.10043.

cr
4. Baker SJ, Tomsho JW, Benkovic SJ. Boron-containing inhibitors of synthetases. Chem

us
Soc Rev. 2011;40(8):4279. doi:10.1039/c0cs00131g.

5.
an
Baker SJ, Ding CZ, Akama T, Zhang Y-K, Hernandez V, Xia Y. Therapeutic potential of

boron-containing compounds. Future Med Chem. 2009;1(7):1275-1288.

M
doi:10.4155/fmc.09.71.

6. Jeong JC, Jambaldorj E, Kwon HY, et al. Desensitization Using Bortezomib and High-
e d

dose Immunoglobulin Increases Rate of Deceased Donor Kidney Transplantation.

pt

Medicine (Baltimore). 2016;95(5):e2635. doi:10.1097/MD.0000000000002635.

ce

7. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone

for Multiple Myeloma. N Engl J Med. 2016;374(17):1621-1634.

Ac

doi:10.1056/NEJMoa1516282.

8. Richardson PG, Hungria VTM, Yoon SS, et al. Panobinostat plus bortezomib and

dexamethasone in previously treated multiple myeloma: Outcomes by prior treatment.

Blood. 2016;127(6):713-721. doi:10.1182/blood-2015-09-665018.

9. Wada Y, Iyoda M, Saito T, et al. Light-Chain Deposition Disease Successfully Treated

 with Bortezomib in an Elderly Patient: A Case Report and Review of the Literature. Intern

Med. 2015;54(22):2893-2898. doi:10.2169/internalmedicine.54.4994.

10. Shah N, Meouchy J, Qazi Y. Bortezomib in kidney transplantation. Curr Opin Organ

Transplant. 2015;20(6):652-656. doi:10.1097/MOT.0000000000000252.

11. Moustafa F, Feldman SR. A review of phosphodiesterase-inhibition and the potential role

for phosphodiesterase 4-inhibitors in clinical dermatology. Dermatol Online J.

t
ip
2014;20(5).
Downloaded by [Australian Catholic University] at 03:11 13 August 2017

12. Del Rosso JQ, Plattner JJ. From the Test Tube to the Treatment Room: Fundamentals of

cr
Boron-containing Compounds and their Relevance to Dermatology. J Clin Aesthet

us
Dermatol. 2014;7(2):13-21. http://www.ncbi.nlm.nih.gov/pubmed/24578778. Accessed

September 19, 2016.

an
13. Beutner K. AN2728 Clinical Data in Atopic Dermatitis. 2012.
M
14. Beutner KR. AN2728 Clinical Data in Psoriasis Overview of AN2728 in Psoriasis Phase

2a ( 201 Study ). 2012.

e d

15. Wigger-Alberti W ZL. Dermal tolerability and preliminary efficacy of AN2728 and
pt

A2898, novel boron-based small molecules, in the treatment of psoriasis. 2011.

ce

16. Akama T, Baker SJ, Zhang YK, et al. Discovery and Structure-Activity Study of a Novel

Benzoxaborole Anti-Inflammatory Agent (AN2728) for the Potential Topical Treatment of

Ac

Psoriasis and Atopic Dermatitis. Vol 19.; 2009. doi:10.1016/j.bmcl.2009.03.007.

17. Dastidar, Sunanda G, Rajagopal, D, Ray A. Therapeutic benefit of PDE4 inhibitors in

inflammatory diseases. Curr Opin Investig Drugs. 2007;8(5):364-372.

18. Jarnagin K, Chanda S, Coronado Bs D, et al. Crisaborole Topical Ointment , 2%: A

Nonsteroidal , Topical , Anti - Inflammatory Phosphodiesterase 4 Inhibitor in Clinical

 Development for the Treatment of Atopic Dermatitis. J Drugs Dermatol. 2016;15(4):390-

396.

19. Freund YR, Akama T, Alley MRK, et al. Boron-based phosphodiesterase inhibitors show

novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012;586(19):3410-3414.

doi:10.1016/j.febslet.2012.07.058.

20. Stephen J. Baker *, Yong-Kang Zhang, Tsutomu Akama, et al. Discovery of a New

t
ip
Boron-Containing Antifungal Agent, 5-Fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole
Downloaded by [Australian Catholic University] at 03:11 13 August 2017

(AN2690), for the Potential Treatment of Onychomycosis. 2006. doi:10.1021/JM0603724.

cr
21. Jinna S, Finch J. Spotlight on tavaborole for the treatment of onychomycosis. Drug Des

us
Devel Ther. 2015;9:6185-6190. doi:10.2147/DDDT.S81944.

22.
an
Rock FL, Mao W, Yaremchuk A, et al. An antifungal agent inhibits an aminoacyl-tRNA

synthetase by trapping tRNA in the editing site. Science. 2007;316(5832):1759-1761.

M
doi:10.1126/science.1142189.

23. Murrell DF, Gebauer K, Spelman L, Zane LT. Crisaborole Topical Ointment, 2% in
e d

Adults With Atopic Dermatitis: A Phase 2a, Vehicle-Controlled, Proof-of-Concept Study.

pt

J Drugs Dermatol. 2015;14(10):1108-1112.

ce

http://www.ncbi.nlm.nih.gov/pubmed/26461821. Accessed September 19, 2016.

24. Stein Gold LF, Spelman L, Spellman MC, Hughes MH, Zane LT. A Phase 2,
Ac

Randomized, Controlled, Dose-Ranging Study Evaluating Crisaborole Topical Ointment,

0.5% and 2% in Adolescents With Mild to Moderate Atopic Dermatitis. J drugs

dermatology. 2015;14(12):1394-1399. http://www.ncbi.nlm.nih.gov/pubmed/26659931.

Accessed September 19, 2016.

25. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a
 novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of

atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-

503.e4. doi:10.1016/j.jaad.2016.05.046.

26. Zane LT, Kircik L, Call R, et al. Crisaborole Topical Ointment, 2% in Patients Ages 2 to

17 Years with Atopic Dermatitis: A Phase 1b, Open-Label, Maximal-Use Systemic

Exposure Study. Pediatr Dermatol. 2016;33(4):380-387. doi:10.1111/pde.12872.

t
ip
27. Zane LT, Hughes MH, Shakib S. Tolerability of Crisaborole Ointment for Application on
Downloaded by [Australian Catholic University] at 03:11 13 August 2017

Sensitive Skin Areas: A Randomized, Double-Blind, Vehicle-Controlled Study in Healthy

cr
Volunteers. Am J Clin Dermatol. June 2016:1-8. doi:10.1007/s40257-016-0204-6.

us
28. Beutner KR, Sanders V HK. An open-label, multi-dose study of the absorption and
an
systemic pharmacokinetics of AN2690 applied as a 7.5% solution to all toenails of adult

patients with moderate to severe onychomycosis. 2007.

M
29. Toledo-Bahena ME, Bucko A, Ocampo-Candiani J, et al. The efficacy and safety of

tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the
e d

topical treatment of toenail onychomycosis. J Drugs Dermatol. 2014;13(9):1124-1132.

pt

http://www.ncbi.nlm.nih.gov/pubmed/25226015. Accessed September 19, 2016.

ce

30. Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical solution,

5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis:
Ac

Results from 2 randomized phase-III studies. J Am Acad Dermatol. 2015;73(1):62-69.

doi:10.1016/j.jaad.2015.04.010.

31. Evans JM, Wang AL, Elewski BE. Successful Treatment of Paecilomyces lilacinus

Onychomycosis with Efinaconazole and Tavaborole. Ski appendage Disord.

2016;1(4):169-171. doi:10.1159/000443773.
 32. Dong C, Virtucio C, Zemska O, et al. Treatment of Skin Inflammation with

Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on

Cytokines Associated with Skin Inflammation and Skin Architecture Changes. J

Pharmacol Exp Ther. 2016;358(3):413-422. doi:10.1124/jpet.116.232819.

33. Ciaravino V, Plattner J, Chanda S. An assessment of the genetic toxicology of novel

boron-containing therapeutic agents. Environ Mol Mutagen. 2013;54(5):338-346.

t
ip
doi:10.1002/em.21779.
Downloaded by [Australian Catholic University] at 03:11 13 August 2017

34. Hui X, Baker SJ, Wester RC, et al. In Vitro Penetration of a Novel Oxaborole Antifungal

cr
(AN2690) Into the Human Nail Plate. J Pharm Sci. 2007;96(10):2622-2631.

us
doi:10.1002/jps.20901.

35.
an
Ciaravino V, Coronado D, Lanphear C, Shaikh I, Ruddock W, Chanda S. Tavaborole, a

novel boron-containing small molecule for the topical treatment of onychomycosis, is

M
noncarcinogenic in 2-year carcinogenicity studies. Int J Toxicol. 2014;33(5):419-427.

doi:10.1177/1091581814545245.
e d

36. Ban HS, Nakamura H. Boron-Based Drug Design. Chem Rec. 2015;15(3):616-635.
pt

doi:10.1002/tcr.201402100.
ce

37. Abeck D, Strom K. Optimal management of atopic dermatitis. Am J Clin Dermatol.

1(1):41-46. http://www.ncbi.nlm.nih.gov/pubmed/11702304. Accessed October 7, 2016.

Ac

38. Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with

atopic eczema. Br J Dermatol. 2000;142(5):931-936.

http://www.ncbi.nlm.nih.gov/pubmed/10809850. Accessed October 7, 2016.

39. Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema.

Health Technol Assess. 2000;4(37):1-191.

 http://www.ncbi.nlm.nih.gov/pubmed/11134919. Accessed October 7, 2016.

40. Yan J, Wang X, Chen S. Systematic review of severe acute liver injury caused by

terbinafine. Int J Clin Pharm. 2014;36(4):679-683. doi:10.1007/s11096-014-9969-y.

41. Madani S, Barilla D, Cramer J, Wang Y, Paul C. Effect of terbinafine on the

pharmacokinetics and pharmacodynamics of desipramine in healthy volunteers identified

as cytochrome P450 2D6 (CYP2D6) extensive metabolizers. J Clin Pharmacol.

t
ip
2002;42(11):1211-1218. http://www.ncbi.nlm.nih.gov/pubmed/12412819. Accessed
Downloaded by [Australian Catholic University] at 03:11 13 August 2017

October 7, 2016.

cr
42. Vickers AE, Sinclair JR, Zollinger M, et al. Multiple cytochrome P-450s involved in the

us
metabolism of terbinafine suggest a limited potential for drug-drug interactions. Drug
an
Metab Dispos. 1999;27(9):1029-1038. http://www.ncbi.nlm.nih.gov/pubmed/10460803.

Accessed October 7, 2016.

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43. Evans JM, Wang AL, Elewski BE. Successful Treatment of Paecilomyces lilacinus

Onychomycosis with Efinaconazole and Tavaborole. Ski appendage Disord.

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2016;1(4):169-171. doi:10.1159/000443773.
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44. Vlahovic T, Coronado D, Chanda S, Merchant T, Zane LT. Evaluation of the Appearance
ce

of Nail Polish Following Daily Treatment of Ex Vivo Human Fingernails With Topical

Solutions of Tavaborole or Efinaconazole. J Drugs Dermatology. 2016;15(1):89-94.

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http://www.ncbi.nlm.nih.gov/pubmed/26741386. Accessed September 19, 2016.

45. Baker SJ, Zhang Y-K, Akama T, et al. Discovery of a New Boron-Containing Antifungal

Agent, 5-Fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the Potential

Treatment of Onychomycosis. J Med Chem. 2006;49(15):4447-4450.

doi:10.1021/jm0603724.
 46. Zhao H, Palencia A, Seiradake E, et al. Analysis of the Resistance Mechanism of a

Benzoxaborole Inhibitor Reveals Insight into the Leucyl-tRNA Synthetase Editing

Mechanism. ACS Chem Biol. 2015;10(10):2277-2285. doi:10.1021/acschembio.5b00291.

Figure Legend

Figure 1: Depiction of a boron atom (B) with its electrons. The red dots are electrons, and the

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blue rings represent the nucleus (innermost ring) and the two electron shells of boron (outer
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rings). The outer shell of boron contains three electrons, which makes boron electron-deficient

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and an electrophile.

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Figure 2. The mechanism of action of crisaborole in atopic dermatitis and psoriasis.
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Crisaborole, a phosphodiesterase 4 (PDE4) inhibitor, prevents the conversion of cyclic AMP

(cAMP) to 5-AMP. Inhibition of this cascade diminishes the release of pro-inflammatory

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cytokines, thus decreasing the severity of atopic dermatitis and/or psoriasis. IFN-, Interferon

gamma; IL-2, Interleukin-2; TNF-, Tumor necrosis factor alpha.

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Figure 3. The mechanism of action of tavaborole. Tavaborole inhibits protein synthesis

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leading to fungus death via intermediate inhibition of fungal leucyl tRNA synthetase. tRNA,
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transfer RNA. The figure was partly generated using somersault18:24 and servier, licensed under

a Creative Commons Attribution 4.0 and 3.0 unported license (available

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atbsomersault1824.com/custom-work/ and servier.com/).

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