J. David Warren

Synthetic carbohydrate-based antitumor vaccines: challenges and opportunities.

The development of a clinically effective, carbohydrate-based antitumor vaccine is a longstanding ambition in the prevention and treatment of cancer. This review seeks to provide a discussion of some of the unique challenges facing this particular field of immunology. The authors present a historic account of their ongoing research program devoted to the development of fully synthetic, carbohydrate-based anticancer vaccines of clinical value. As will be seen, remarkable advances in carbohydrate and glycopeptide assembly techniques have allowed for the preparation of synthetic constructs of progressively increasing structural complexity. The authors describe the evolution of their synthetic carbohydrate program from first-generation constructs, which were monovalent in nature, to highly complex unimolecular multivalent vaccines, in which multiple carbohydrate antigens are displayed in the context of a single polypeptide backbone. It is the hope that each generation of vaccines represents a move closer to achieving the ultimate objective of developing broadly useful, robust anticancer vaccines.

Synthetic Glycopeptide-Based Vaccines

This review provides an overview of our explorations into oligosaccharide and glycoconjugate construction for the creation and evaluation of glycopeptide-based vaccines. The basis for these investigations is the known tendency of both cancer cells and viruses to express selective carbohydrate motifs in the form of glycoproteins or glycolipids. Utilization of these carbohydrates in a glycopeptide-based vaccine could potentially trigger immune recognition, generating a protective response against the disease. However, obtaining large quantities of such compounds from natural sources is extremely difficult. Over the past two decades, our lab has been engaged in the total synthesis of complex oligosaccharides and glycoconjugates. With this knowledge and experience, we have begun to evaluate, in many cases at the clinical level, whether the human immune system is capable of mounting a response against such fully synthetic carbohydrate antigens in a focused and useful way. Toward this goal, we have merged the powers of both chemistry and immunology to provide insight into this problem. The synthesis and evaluation of potential vaccines for both cancer and HIV will be described.

Cooperation between a Coenzyme A-Independent Stand-Alone Initiation Module and an Iterative Type I Polyketide Synthase during Synthesis of Mycobacterial Phenolic Glycolipids

Several Mycobacterium tuberculosis strains, Mycobacterium leprae, and other mycobacterial pathogens produce a group of small-molecule virulence factors called phenolic glycolipids (PGLs). PGLs play key roles in pathogenicity and host−pathogen interaction. Thus, elucidation of the PGL biosynthetic pathway will not only expand our understanding of natural product biosynthesis, but may also illuminate routes to novel therapeutics to afford alternative lines of defense against mycobacterial infections. In this study, we report an investigation of the enzymatic requirements for the production of long-chain p-hydroxyphenylalkanoate intermediates of PGL biosynthesis. We demonstrate a functional cooperation between a coenzyme A-independent stand-alone didomain initiation module (FadD22) and a 6-domain reducing iterative type I polyketide synthase (Pks15/1) for production of p-hydroxyphenylalkanoate intermediates in in vitro and in vivo FadD22-Pks15/1 reconstituted systems. Our results suggest that Pks15/1 is an iterative type I polyketide synthase with a relaxed control of catalytic cycle iterations, a mechanistic property that explains the origin of a characteristic alkyl chain length variability seen in mycobacterial PGLs. The FadD22-Pks15/1 reconstituted systems lay an initial foundation for future efforts to unveil the mechanism of iterative catalysis control by which the structures of the final products of Pks15/1 are defined, and to scrutinize the functional partnerships of the FadD22-Pks15/1 system with downstream enzymes of the PGL biosynthetic pathway.