Carbohydrate-based anti-infective agents can disrupt complex carbohydrate recognition events vital to the infective mechanisms of pathogens, representing an untapped wealth of therapeutics. The promise of carbohydrate-based anti-infective is that they are less prone to the evolution of microbial resistance, because, carbohydrate ligands themselves are invariant, and carbohydrate recognition is essential to pathogenic function. As such, carbohydrate-based anti-infective can better thwart the looming public health threats posed by the evolution of resistant microbial strains. The goals of the proposed research are to specifically develop new carbohydrate-based anti-infective agents that address the recent rise of resistant strains of pathogenic bacteria and influenza, as detailed in two aims targeting: 1) bacterial transglycosylase, and 2) the influenza coat proteins hemagglutinin and neuraminidase. Transglycosylase (TGase) is the enzyme responsible for assembling the carbohydrate backbone of the bacterial cell wall: it is essential, accessible, and less prone to evolving antibiotic resistance due to its recognition of the invariant oligosaccharide backbone of the peptidoglycan. Our efforts have primed TGase for long-awaited antibiotic development against dangerous gram-positive strains of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). In extension, the Mycobacterial TGase will be established for the development of anti-tuberculosis agents, which are in great need due to the alarming rise of multi- and extensively-drug resistant Mycobacterium tuberculosis (MDR-/XDR-TB). Routes for the specialized synthesis of carbohydrate-based substrate analogs, transition state inhibitors, and novel drug- like motifs are proposed for targeting gram-positive and Mycobacterial TGases. Hemagglutinin (HA) and neuraminidase (NA) are influenza coat glycoproteins that are susceptible to inhibition by sialic acid derivatives, which interfere with necessary recognition of sialosides (i.e. complex carbohydrates that end with a sialic acid). They are also targets of the adaptive immune response, which can generate neutralizing antibodies to antigenic protein epitopes, particularly with HA. Strategies for inhibition and immunization need to be improved, as high rates of viral mutation lead to resistance against antiinfluenza agents (e.g., the rapid emergence of Tamiflu resistant "swine flu" during the 2009 level-6 pandemic outbreak) and antigenic drift (i.e., escape from protective immunity). Looming pandemic threats further hasten this need. Antiinfluenza agents are designed herein with focus on establishing a higher barrier to resistance and understanding how resistant mutations affect NA-sialoside interactions. A strategy for a carbohydrate-modified HA protein vaccine is presented, with attention directed toward maximizing cross-reactive immunity.
Anti-infective agents are essential to preserving public health, but are increasingly compromised by the evolution of microbial resistance. This proposal is centered on developing carbohydrate-based anti-infective agents that can disrupt or exploit invariant carbohydrate recognition processes critical to pathogen survival and infectivity, leading to important new therapeutics for effectively managing infectious disease, while minimizing problems associated with microbial resistance. In this revised competing resubmission, two of the largest microbial resistance problems of concern to public health are addressed: first, new antibiotics are developed targeting transglycosylase, which assembles the essential and highly conserved carbohydrate backbone of the bacterial cell wall;second, new antiinfluenza agents are developed targeting the influenza coat proteins hemagglutinin and neuraminidase, which are dependent on the recognition of sialoside carbohydrate receptors for infectivity.
|Hsu, Che-Hsiung; Park, Sangho; Mortenson, David E et al. (2016) The Dependence of Carbohydrate-Aromatic Interaction Strengths on the Structure of the Carbohydrate. J Am Chem Soc 138:7636-48|
|Shivatare, Sachin S; Chang, Shih-Huang; Tsai, Tsung-I et al. (2016) Modular synthesis of N-glycans and arrays for the hetero-ligand binding analysis of HIV antibodies. Nat Chem 8:338-46|
|Hsu, Che-Hsiung; Schelwies, Mathias; Enck, Sebastian et al. (2014) Iminosugar C-glycoside analogues of Î±-D-GlcNAc-1-phosphate: synthesis and bacterial transglycosylase inhibition. J Org Chem 79:8629-37|
|Chen, Wentao; Enck, Sebastian; Price, Joshua L et al. (2013) Structural and energetic basis of carbohydrate-aromatic packing interactions in proteins. J Am Chem Soc 135:9877-84|
|Doores, Katie J; Huber, Michael; Le, Khoa M et al. (2013) 2G12-expressing B cell lines may aid in HIV carbohydrate vaccine design strategies. J Virol 87:2234-41|
|Al-Shareffi, Esam; Chaubard, Jean-Luc; Leonhard-Melief, Christina et al. (2013) 6-alkynyl fucose is a bioorthogonal analog for O-fucosylation of epidermal growth factor-like repeats and thrombospondin type-1 repeats by protein O-fucosyltransferases 1 and 2. Glycobiology 23:188-98|
|Lenger, Janina; Schroder, Marius; Ennemann, Eva C et al. (2012) Evaluation of sulfatase-directed quinone methide traps for proteomics. Bioorg Med Chem 20:622-7|
|Price, Joshua L; Culyba, Elizabeth K; Chen, Wentao et al. (2012) N-glycosylation of enhanced aromatic sequons to increase glycoprotein stability. Biopolymers 98:195-211|
|Culyba, Elizabeth K; Price, Joshua L; Hanson, Sarah R et al. (2011) Protein native-state stabilization by placing aromatic side chains in N-glycosylated reverse turns. Science 331:571-5|
|Schelwies, Mathias; Brinson, Diana; Otsuki, Shuhei et al. (2010) Glucosamine-6-sulfamate analogues of heparan sulfate as inhibitors of endosulfatases. Chembiochem 11:2393-7|
Showing the most recent 10 out of 14 publications