Designing inhibitors of anthrax toxin

Abstract

Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals with anti-PA therapeutics can be time-dependent, requiring coordinated use of membrane permeable small-molecule inhibitors, which block the LF and EF enzymatic activity intracellularly. The desperate search for an ideal anthrax antitoxin allowed researchers to gain important knowledge of the basic principles of small-molecule interactions with their protein targets that could be easily transferred to other systems. At the same time, better identification and validation of anthrax toxin therapeutic targets at the molecular level, which include understanding of the physical forces underlying the target/drug interaction, as well as elucidation of the parameters determining the corresponding therapeutic windows, require further examination.

Pore-forming activity of clostridial binary toxins

“…Excellent reviews have addressed pore blocker molecules and their ability to inhibit PFTs [119,128]. Two families, small cationic blockers and cationic cyclodextrin derivatives, have been mainly investigated.…”

Anti-virulence Strategies to Target Bacterial Infections

“…For instance, several potent inhibitors have been identified for the Bacillus anthracis-encoded anthrax toxin, a multimeric toxin consisting of three proteins, the protective antigen (PA), the edema factor (EF) and the lethal factor (LF) (Montecucco et al 2004;Nestorovich and Bezrukov 2014;Tonello et al 2002). The PA binds to the host cell surface, where it gets cleaved and forms multimeric channels in the host cell membrane through which the EF and the LF can enter the cell.…”

Development of Specific Therapy to Category A ToxicInfections

“…Это не только затрудняет разработку специфических низкомолекулярных инги-биторов ЛФ, но и поиск новых мишеней этой протеа-зы, существенная часть которых практически наверняка осталась не идентифицированной [22,23]. Последние необходимы для эффективной блокировки действия ЛТ наряду с моноклональными антителами, поскольку анти-тельные препараты не способны проникать внутрь клетки для нейтрализации уже транслоцированного в цитозоль ЛФ [24].…”