Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843-2128, USA.
Calico Life Sciences LLC, 1170 Veterans Blvd, South San Francisco, CA 94080, USA.
Int J Mol Sci. 2021 Jun 23;22(13):6754. doi: 10.3390/ijms22136754.
The emergence of fungal "superbugs" resistant to the limited cohort of anti-fungal agents available to clinicians is eroding our ability to effectively treat infections by these virulent pathogens. As the threat of fungal infection is escalating worldwide, this dwindling response capacity is fueling concerns of impending global health emergencies. These developments underscore the urgent need for new classes of anti-fungal drugs and, therefore, the identification of new targets. Phosphoinositide signaling does not immediately appear to offer attractive targets due to its evolutionary conservation across the Eukaryota. However, recent evidence argues otherwise. Herein, we discuss the evidence identifying Sec14-like phosphatidylinositol transfer proteins (PITPs) as unexplored portals through which phosphoinositide signaling in virulent fungi can be chemically disrupted with exquisite selectivity. Recent identification of lead compounds that target fungal Sec14 proteins, derived from several distinct chemical scaffolds, reveals exciting inroads into the rational design of next generation Sec14 inhibitors. Development of appropriately refined next generation Sec14-directed inhibitors promises to expand the chemical weaponry available for deployment in the shifting field of engagement between fungal pathogens and their human hosts.
真菌“超级细菌”的出现对临床可用的有限数量的抗真菌药物具有抗药性，这正在削弱我们有效治疗这些致命病原体感染的能力。随着真菌感染的威胁在全球范围内不断升级，这种反应能力的下降引发了对即将到来的全球卫生紧急情况的担忧。这些发展情况突显了开发新型抗真菌药物的迫切需求，因此也需要确定新的靶标。由于磷酸肌醇信号在真核生物中具有进化保守性，因此其似乎不能立即提供有吸引力的靶标。然而，最近的证据表明并非如此。在此，我们讨论了将 Sec14 样磷脂酰肌醇转移蛋白（PITP）鉴定为未被探索的门户的证据，通过该门户可以通过化学方法极其选择性地破坏毒力真菌中的磷酸肌醇信号。最近从几种不同化学支架中鉴定出针对真菌 Sec14 蛋白的先导化合物，为合理设计下一代 Sec14 抑制剂开辟了令人兴奋的途径。适当改进的下一代 Sec14 定向抑制剂的开发有望扩大可用于真菌病原体与其人类宿主之间不断变化的作用领域的化学武器库。
