UCSF

Nature challenges healthy mammals with constant risk of infection by a wide variety of pathogens and with degradation of healthy tissue and control systems. I have been interested in drug delivery and improved delivery of therapeutics primarily to attack pathogens but with incidental value in assessing vital functions of a healthy mammal. My recent work uses protein design to approach such problems. Delivering biomacromolecules remains important both for therapeutics and in discerning and shaping functions of cells.My first thesis project focused on designing a better glomerular filtration rate (GFR) marker to facilitate assessment of renal function and seeking a marker reflecting water distribution in the body, which is relevant to distribution of highly soluble drugs [1]. Tritiated polyethylene glycol (PEG) was known to clear the kidneys effectively and correlated well with a GFR standard assay. A better radioactive label for PEG would allow for easy detection, including imaging. At the time of the project, only one biological conjugation with PEG was reported. Attaching an iodinatable moiety to polyethylene glycol (PEG) polymers of different sizes enabled tracking the compound using radioactive iodine. I made a series of related compounds and studied the pharmacokinetics (PK) and pharmacodynamics (PD) of these in rodents and ultimately in a dog. Using relatively long PEG polymers of molecular weight (MW) 5,000 to 6,000 daltons, the PEG dominated the behavior of the compounds, clearing rapidly through the kidneys. With shorter PEG polymers, the chemistry of the iodinatable group was more significant and the compounds were more likely to clear through the bile, to a degree making them unsuitable for a GFR marker but possibly useful to study liver function. Chapter 1, the published manuscript from my first thesis project, is cited in 20 scientific publications and 51 issued US patents. Variations on the design principles of my project have been used widely in the pharmaceutical industry. During a break in my PhD studies, I improved the formulation of a human Phase-2-ready antifungal drug and designed and organized extensive testing in mice and dogs to show that a sustained-release formulation would overcome PK limitations and made the drug much more potent. This work is discussed briefly in Chapter 2. My second thesis project studied brilacidin activity against 40 fungal isolates from 20 different species, showing useful activity against several important human pathogens [2]. The human and many other innate immune systems includes a variety of peptides known as defensins that weaken or kill a variety of pathogens, including bacteria, fungi, and viruses. Brilacidin is a synthetic defensin-mimic, designed to exhibit the physicochemical properties of defensins as a class. Brilacidin is in human Phase 2 trials. Despite its potential, Brilacidin's efficacy against fungi had not been comprehensively explored until my studies, which showcased its viability as a therapeutic agent against challenging-to-treat fungal infections, thereby offering a beacon of hope for future clinical interventions. Chapter 3, the published manuscript based on this second thesis project, has recently been submitted for review, available online in Preprints.