ABSTRACT
The COVID-19 outbreak has highlighted the importance of pandemic preparedness for the prevention of future health crises. One virus family with high pandemic potential are Arenaviruses, which have been detected almost worldwide, particularly in Africa and the Americas. These viruses are highly understudied and many questions regarding their structure, replication and tropism remain unanswered, making the design of an efficacious and molecularly-defined vaccine challenging. We propose that structure-driven computational vaccine design will contribute to overcome these challenges. Computational methods for stabilization of viral glycoproteins or epitope focusing have made progress during the last decades and particularly during the COVID-19 pandemic, and have proven useful for rational vaccine design and the establishment of novel diagnostic tools. In this review, we summarize gaps in our understanding of Arenavirus molecular biology, highlight challenges in vaccine design and discuss how structure-driven and computationally informed strategies will aid in overcoming these obstacles.
ABSTRACT
Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the "foot-pocket" in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D7.4 ) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising "capless" HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10 c (LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines.
