Pharmacological Reviews最新文献

For most vertebrates, bitter perception plays a critical role in the detection of potentially harmful substances in food items. The detection of bitter compounds is facilitated by specialized receptors located in the taste buds of the oral cavity. This work focuses on these receptors, including their sensitivities, structure-function relationships, agonists, and antagonists. The existence of numerous bitter taste receptor variants in the human population and the fact that several of them profoundly affect individual perceptions of bitter tastes are discussed as well. Moreover, the identification of bitter taste receptors in numerous tissues outside the oral cavity and their multiple proposed roles in these tissues are described briefly. Although this work is mainly focused on human bitter taste receptors, it is imperative to compare human bitter taste with bitter taste of other animals to understand which forces might have shaped the evolution of bitter taste receptors and their functions and to distinguish apparently typical human features from rather general ones. For readers who are not very familiar with the gustatory system, short descriptions of taste anatomy, signal transduction, and oral bitter taste receptor expression are included in the beginning of this article. SIGNIFICANCE STATEMENT: Apart from their role as sensors for potentially harmful substances in the oral cavity, the numerous additional roles of bitter taste receptors in tissues outside the gustatory system have recently received much attention. For careful assessment of their functions inside and outside the taste system, a solid knowledge of the specific and general pharmacological features of these receptors and the growing toolbox available for studying them is imperative and provided in this work.

Male factor infertility is a multifaceted problem that affects approximately 50% of couples suffering from infertility. Causes of male infertility include endocrine disturbances, gonadotoxins, genetic abnormalities, varicocele, malignancies, infections, congenital or acquired urogenital abnormalities, iatrogenic factors, immunological factors, and idiopathic reasons. There are a variety of treatment options for male infertility, depending on the underlying cause(s). These can include surgical treatments, medical/hormonal therapies, and assisted reproductive techniques (ART), which can be combined with surgical sperm retrieval (SSR) if necessary. In this review article, the pharmacological therapies for male infertility are grouped by their underlying causes. Some of these therapies are targeted and specific, while others are used empirically to treat idiopathic male infertility. This will include treatments to optimize infertility in patients who have hypogonadism, ejaculatory dysfunction, infections, or idiopathic male infertility. Finally, we will provide an overview of the future directions of pharmacological therapies for male infertility. Significance Statement Male infertility is a significant worldwide problem. Detailed knowledge of the pharmacological therapies available will ensure the prescription of appropriate therapy and avoid the use of unnecessary or harmful treatments.

Biologically active proteins/regions without stable structure (i.e., intrinsically disordered proteins and regions (IDPs and IDRs)) are commonly found in all proteomes. They have a unique functional repertoire that complements the functionalities of ordered proteins and domains. IDPs/IDRs are multifunctional promiscuous binders capable of folding at interaction with specific binding partners on a template- or context-dependent manner, many of which undergo liquid-liquid phase separation, leading to the formation of membrane-less organelles and biomolecular condensates. Many of them are frequently related to the pathogenesis of various human diseases. All this defines IDPs/IDRs as attractive targets for the development of novel drugs. However, their lack of unique structures, multifunctionality, binding promiscuity, and involvement in unusual modes of action preclude direct use of traditional structure-based drug design approaches for targeting IDPs/IDRs, and make disorder-based drug discovery for these "protein clouds" challenging. Despite all these complexities there is continuing progress in the design of small molecules affecting IDPs/IDRs. This article describes the major structural features of IDPs/IDRs and the peculiarities of the disorder-based functionality. It also discusses the roles of IDPs/IDRs in various pathologies, and shows why the approaches elaborated for finding drugs targeting ordered proteins cannot be directly used for the intrinsic disorder-based drug design, and introduces some novel methodologies suitable for these purposes. Finally, it emphasizes that regardless of their multifunctionality, binding promiscuity, lack of unique structures, and highly dynamic nature, "protein clouds" are principally druggable. Significance Statement Intrinsically disordered proteins and regions are highly abundant in nature, have multiple important biological functions, are commonly involved in the pathogenesis of a multitude of human diseases, and are therefore considered as very attractive drug targets. Although dealing with these unstructured multifunctional protein/regions is a challenging task, multiple innovative approaches have been designed to target them by small molecules.