Tavaborole | Treatment of Onychomycosis | Leucyl-tRNA Synthetase Inhibitor

Tavaborole [5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole] is a novel, small molecule oxaborole antifungal developed for the topical treatment of onychomycosis of the toenail. In 2014, the drug received its first global approval for this indication in the US. 

Tavaborole exerts its antifungal activity by blocking cellular protein synthesis via inhibition of yeast cytoplasmic leucyl-aminoacyl transfer RNA (tRNA) synthetase. The inhibition of protein synthesis leads to termination of cell growth and then cell death, eliminating the fungal infection.

Tavaborole: 2D and 3D Structure

In in vitro studies, Tavaborole showed minimal inhibitory concentrations (MICs) of 1-8 ug/mL against the dermatophytes T. mentagrophytes and T. rubrum (the primary causative agents of onychomycosis). Tavaborole was fungicidal against T. rubrum and T. mentagrophytes with minimum fungicidal concentrations (MFC₅₀) of 64 ug/mL [1, 2].

Treatment for Onychomycosis

Subungual onychomycosis is difficult to treat due to the poorly perfused location of the infection. To be effective, a topical treatment must penetrate the nail plate and reach the site of infection at a concentration sufficient to exert antifungal activity.  Tavaborole a novel, low molecular weight (151.9 Da) oxaborole antifungal drug has been shown to penetrate the nail after topical application at concentrations sufficient to inhibit the primary causative fungi of onychomycosis. 

Toenails are more commonly affected than fingernails: onychomycosis in these cases frequently involves several nails, and dry-type plantar tinea pedis is often present [3]. There are different clinical types of onychomycosis, depending on the modality of nail invasion. Clinical diagnosis of onychomycosis always requires laboratory confirmation, and treatment depends on many factors, like the fungus species and the number of affected nails.

Tavaborole exerts its antifungal activity by blocking cellular protein synthesis via inhibition of yeast cytoplasmic leucyl-aminoacyl transfer RNA (tRNA) synthetase. Formation of a stable tRNA^Leu-tavaborole adduct (resulting from the boron atom of the oxaborole ring binding to the 2’, 3’-hydroxy groups on the tRNA 3’-terminal adenosine) inhibits leucyl-tRNA^Leu synthesis, consequentially blocking protein synthesis. Tavaborole analogs where boron was replaced with carbon had no activity, demonstrating the boron atom in the oxaborole ring is essential for the drugs mechanism of fungal inhibition.

Tavaborole against Dermatophytes:

 In in vitro studies, Tavaborole showed minimal inhibitory concentrations (MICs) of 1-8 ug/mL against the dermatophytes T. mentagrophytes and T. rubrum (the primary causative agents of onychomycosis) and of less than 0.5-4 ug/mL against Trichophyton tonsurans, Epidermophyton floccosum, Microsporum audouinii, Microsporum canis and Microsporum gypseum.

Tavaborole was also active against Aspergillus fumigatus, Candida spp., Cryptococcus neoformans, Fusarium solani, Malassezia spp. and Saccharomyces cerevisiae with MIC values of between 0.25 and 1 u/mL. Tavaborole was fungicidal against T. rubrum and T. mentagrophytes with minimum fungicidal concentrations (MFC₅₀) of 64 ug/mL.

The presence of 5 % powdered keratin had no effect on the microbiological activity of the drug against T. rubrum.

Dosages and Approval:

Tavaborole as 5% topical solution (Trademark: Kerydin) has been approved in by the US Food and Drug Administration (FDA) in 2014 for the treatment of onychomycosis of the toenails caused by Trichophyton mentagrophytes or Trichophyton rubrum.

Tavaborole was discovered and developed by Anacor pharmaceuticals. In early 2007 Anacor entered into an exclusive worldwide licensing agreement with Schering-Plough Corporation (now a subsidiary of Merck) for the development and commercialisation of Tavaborole, which led to the two companies successfully manufacturing the product candidate and completing certain phase III development activities. In February 2010, Merck returned full worldwide development and commercialisation rights for the drug to Anacor.

Tavaborole Synthesis

US5880188A: It is one of the oldest reported synthetic procedure.

Tetrahedron 2007, 63, 9401-9405: A convenient one-pot synthesis of Tavaborole has been developed via the reaction of o-bromobenzyl alcohols with NaH, n-BuLi, and B(O-ⁱPr)₃.

J Med Chem 2006, 49(15), 4447-4450: The article reports an industrially viable synthetic procedure. It also reports synthesis for various Tavaborole analogues, along-with activity against various strains.

Identifications:

Experimental: ¹H NMR (300MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J = 9.7, 1.8 Hz, 1H), 7.74 (dd, J = 8.2, 6.2 Hz, 1H), 9.22 (s, 1H).

Sideeffects: The most common adverse event (AE) reported was topical irritation; application site reactions were generally mild to moderate in severity and reversible. Adverse events occurring in greater than 5 % of patients regardless of relationship to treatment included influenza, pharyngitis, tinea pedis, upper respiratory tract infection, tooth abscesses, gastroenteritis and peripheral oedema.

References:

1. Markham, A. Tavaborole: First Global Approval. Drugs 2014, 74(13), 1555-1558. (FMO only)

2. Rock, F. L.; et. al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 2007, 316(5832), 1759-1761. (FMO only)
3. Piraccini, B. M.; et. al. Onychomycosis: A Review. J Fungi 2015, 1(1), 30-43. (free copy)

4. Austin, P. W.; et. al. Oxaboroles and salts thereof, and their use as biocides. US5880188A

5. Gunasekera, D. S.; et. al. Practical synthesis and applications of benzoboroxoles. Tetrahedron 2007, 63, 9401-9405. (FMO only)
6. Baker, S. J.; 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. (FMO only)