Basic Research

Since its discovery from the extracts of sweet wormwood (Artemisia annua) in 1979. the anti-malarial drug artemisinin (3) is now the key starting material in the synthesis of life-saving artemisinin-based combination therapies (ACT). Yet. beginning in 2009. mutations in the parasites PfKelch13 protein began conferring artemisinin resistance in the Greater Mekong Subregion (GMS) (Figure 1).Since then. artemisinin resistance has been spreading and some ACT treatment failure rates have reached 26% to 46% in 2015.

COVID-19. a debilitating disease. represents the single major world-wide health issue that needs to be addressed urgently. The severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2). the causative agent of COVID-19. is a highly infectious virus for whichthere is no effective treatment. Entry of enveloped viruses such as SARS-CoV-2. into their host cells involves several steps that can be targeted individually for therapeutic intervention.including protein-protein interactions between viral proteins and host cell receptors. A protein called Glycoprotein-S.

The central hypothesis of this research project is that rheostat positions have general properties that distinguish them from other nonconserved positions. In Aim 1. we will test the hypothe- sis that rheostat positions can be detected by a particular pattern of evolutionary change. using pyruvate kinase. aldolase. and an organic anion transmembrane transporter as model systems. If prediction is possible. amino acid variants at rheostat positions should be ??? for now ??? classified as having ???unknown significance??? to reduce false predictions. Further.

Basic Research

This basic science research will lay the necessary foundation for future novel antimicrobial drug design efforts. Opine metallophores are recently identified novel metal acquisition small molecules made by diverse bacterial pathogens: Staphylococcus aureus. Pseudomonas aeruginosa. and Yersinia pestis. The operons for biosynthesis. export and re-uptake have only been reported in the last two years. and yet these systems have already been shown to be linked to pathogenesis in mouse models for bacteremia. lung infections and burn wound infections.

Basic Research

Cytokine storm or macrophage activation syndrome (MAS; (1)) leads to secondary haemophagocytic lymphohistiocytosis (sHLH) and a deadly sepsis-like multi-organ failure in severe viral infections (2.3). including COVID-19 (4.5). Currently there are no established safe and effective therapies against MAS (5.6). It is accepted that an improper interplay between pro- inflammatory (M1) and anti-inflammatory (M2) macrophages (7) is. in part. responsible for MAS. M1s are activated early during infection and secrete the ???storm??? of cytokines leading to hyper inflammation (8). Then.

This research project will seek to answer if the allosteric site in one subunit regulates the active site in the same subunit. a result that will simplify mechanistic interpretation of structural changes. Detailed understanding of the molecular mechanisms of hL-PYK will facilitate future drug designs to activate (or prevent inhibition of) this enzyme to reduced hepatic glucose secretion and counteract hyperglycemia.In both type 1 and type 2 diabetes. hepatic secretion of glucose is a primary contributor to hyperglycemia. In turn.