Tropical diseases, notably orthoflaviviral infections (e.g., DENV, ZIKV, and WNV) and malaria, significantly challenge health systems, especially in low and middle-income countries, contributing to high mortality rates and perpetuating poverty. The absence of treatment or the emerging resistance to current therapies necessitates the development of novel and effective drugs. This thesis investigates the design, synthesis, and evaluation of new anti-orthoflaviviral and antimalarial agents, respectively peptidomimetic lipopeptides and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines (THIP).
The anti-orthoflaviviral lipopeptides, derived from the optimization of geminoid compounds initially developed as transfection agents, demonstrated inhibition of the orthoflaviviral protease NS2B-NS3 and DENV infection in vitro. Iterative design, sequence, and C-terminal modifications led to significant advancements in understanding the structure-activity relationships (SARs) of these compounds, with selected derivatives showing promising antiviral activity and good cell viability which prompted in vivo studies.
The THIP scaffold, discovered through high-throughput screening, underwent extensive optimization, resulting in derivatives with potent antimalarial activity against various stages of the Plasmodium life cycle. Systematic synthesis and biological evaluation provided valuable SAR insights, guiding future development.
The thesis highlights the progression of selected compounds to pre-clinical stages, demonstrating their potential as therapeutic agents for DENV and malaria, ultimately contributing to the broader scientific effort to combat tropical diseases.
Lorenzo Cavina pursued a BSc in Chemistry at the University of Bologna, where he researched medicinal chemistry in the L.Gentilucci group, designing and synthesizing small cyclic peptides as opioid antinociceptives. He continued therein as a graduate researcher, extending his work to non-natural amino acids and peptidomimetics.
He obtained his MSc from the Radboud University Nijmegen, where interned at the pharmaceutical spin-off Chiralix, designing and synthesizing pantothenamide analogues for antimalarial and antibacterial applications, and at the Scripps Research Institute (FL), under S.Snyder, where he optimized the synthesis of the alkaloid Scholarisine A. He published a review on medicinal chemistry.
In his doctoral studies at the Radboud University he collaborated with Protinhi Therapeutics and TropIQ Healthsciences. Within the Synthetic Organic Chemistry (Rutjes) group he optimized peptide-based antivirals for DENV and antimalarials for Plasmodium, resulting in a patent. Currently, he is a postdoctoral researcher within the RU/RUMC designing and synthesizing PROTACs against leukemia.