By Anthony L. Almada, MSc, FISSN
Just before 1990 (that just reads so distant, so old.) I was deep into exercise biochemistry, having just finished my graduate research thesis at UC Berkeley (with adoring female rats as my subjects) and began to collaborate on my first university-based clinical trials. A few of the then hot sport nutrition supplements were ultra simple and cheap: sodium bicarbonate and sodium citrate. The presumed mechanism (back then) was cool: ingest enough of either ingredient to buffer acidification of the muscle during intense exercise and go stronger/faster, longer. Their simplicity failed to capture my curiosity but another buffer—present in muscle, made in the body, and found in the diet did: L-carnosine. I read this paper at least ten times, and hunted down every other L-carnosine paper, before and after, old school style: by hand searching and page turning in the stacks at UC San Francisco Medical Library (long before the advent of internet–enabled searching of biomedical journals).
L-carnosine is two amino acids connected by a distinct chemical (peptide) bond—it is thus categorized as a dipeptide, the di- prefix relating to two. One of the amino acids (L-histidine) is present in effectively every dietary protein and the other—beta-alanine (B-A), as of yet not identified in dietary or human proteins. Histidine is essential to human nutrition—it cannot be made in adequate quantities and thus must be provided in the diet. B-A, however, can be made de novo in human metabolism. B-A has assumed a place in the performance nutrition elite power tool box, largely a result of the assiduous pursuit of its metabolism, disposition, and whole body and skeletal muscle effects by Professor Roger Harris, who also was the “co-discoverer” of creatine monohydrate (along with the late, great Professor Eric Hultman), with enduring financial support from, and patent enforcement activities underwritten by, Natural Alternatives, Inc (under the CarnoSyn® brand).
After reading the aforementioned muscle buffer study I began to look for a source of L-carnosine as an ingredient to sell to performance nutrition companies (this predated my co-founding Experimental and Applied Sciences—formerly known as “EAS”—by at least three years). I found a source in Japan but it was prohibitively expensive and a study in ratsgnawed a hole in my hope balloon, indicating that this mini-peptide could elude extensive digestion in the gut, enter the blood intact, and produce a meaningful increment in skeletal muscle L-carnosine content. I relented to rodent research and put my tail between my legs.
Fast forward about a decade.
Turn of the century. 2000, BS (Before Social [media]): my computer keyboard was surfing in Japan—a lot. Not at Tsurigasaki Beach (the home break for the birth of surfing as an Olympic sport, in 2020) but around a chemical & pharmaceutical company: Hamari Chemicals, Ltd. in Osaka. My recently minted consulting company (IMAGINutrition, Inc.) had landed a fantastic new (and big) client: Lonza (with global HQ in Basel, Switzerland). Lonza was known in the dietary ingredient world primarily for its L-carnitine (tartrate; CarniPure®), another non-protein amino acid (like B-A). My new contact there was Dan Murray, and the mission he charged me with was to put assemble a clinical trial for L-carnosine. I reached out to my now good friend Prof. Harris, the discussions began, and the protocol was developed. In parallel, in preparation for writing the clinical trial protocol I dove deep and wide into the carnosine science. I was initially disturbed to see citations bearing what I thought was a typo: polaprezinc. Polarzinc? What is that? It even had a drug code name: Z-103.
It was no typo: polaprezinc was and remains a generic chemical name for zinc L-carnosine. The inventors were a team at a Japanese (Osaka) chemical/active pharmaceutical ingredient company called Hamari and they had assembled (even back then) a compelling package: issued patents on the actual molecule (polaprezinc is more complex than it reads—see below), over half a dozen rigorous toxicology and metabolism studies in animals (all published by 1991), and even a few clinical trials. A Japanese pharmaceutical brand (Zeria Pharmaceutical, hence the ‘Z‘ in Z-103) had sponsored the animal tox studies and some of the pilot clinical trials and was marketing it for upper GI health (that is, the stomach/upper gut, hence this article’s title “Probiotic Gap Filler”, as the vast majority of the evidence base for strain-specific probiotics targets the lower, sub-small intestine GI region…).
Chemistry begets biology.
Polaprezinc is actually a small polymer (oligomer) of zinc-L-carnosine subunits, an organometallic complex that delivers zinc in a delayed/extended release manner (possibly due to its very low solubility). The majority of the animal studies that compared polaprezinc to zinc salts e.g. zinc sulfate showed greater efficacy with polaprezinc, as did polaprezinc when compared to L-carnosine alone. In Spain, a different zinc complex, zinc bis-acexamate (a complex of zinc and two [‘bis’] acexamic acid molecules; this is a prescription drug for human stomach ulcers and GastroEsophageal Reflux Disease AKA GERD) is marketed under the brand name Copinal®.
The chemical structure of polaprezinc/PepZin GI is challenging: the zinc atom is coordinated by four different chemical connections, thus polaprezinc is considered to be a tetradentate (four teeth biting on zinc) complex. Add in the observation that small polymers of polaprezinc/PepZin GI are formed during its manufacture and you arrive at a very intriguing dietary ingredient. These polymers are comprised of 2-3 or more repeating polaprezinc molecules; the ‘n’ in the bottom right of the image below relates to a non-specific number of repeating zinc-L-carnosine molecules forming a chain or polymer.
Polaprezinc: three “teeth” around the Zn (Zinc) atom, the bottom arrow indicating where the fourth tooth–from another polaprezinc “monomer” would “bite” (the top left arrow coming off the N (Nitrogen atom) to form a polymer.
My amateur attempt to (very loosely) depict how one polaprezinc monomer would attach to another and create a tetradentate (four teeth around the Zn atom) oligomer of polaprezinc.
I presented polaprezinc and the data/IP package to Dan Murray and he saw the promise: he took it up the food chain in Basel. I teed up a call between Lonza and Hamari and it resulted in a territorial exclusive patent license and supply agreement. I came up with the name PepZin GI® and worked with my talented graphic designer friend Neil Beltran to craft a logo and brand identity kit. Lonza smartly orchestrated and submitted a New Dietary Ingredient notice to FDA in May, 2002, which was allowed in July, 2002 and announced in September, 2002.
The original PepZin GI logo (superscript ™ before the ® was granted). Circa Q4, 2002.
After this Dan and I engaged my quintessentially French friend, chef, wine connoisseur, research scientist, and physician, Dr. Georges Halpern to write a consumer book all about zinc-L-carnosine. Dan and I also reached out to Dr. Ray Playford (then in the Gastroenterology Department at Imperial College in London) to provide some industrial seminars about PepZin GI and we began laying the plans for a PepZin GI clinical trial outside of Japan (more about that, and the leaky gut link, in Part II of this series).
In addition to being the only legally saleable zinc-L-carnosine ingredient in the USA (because of its NDI allowance), PepZin GI’s unique chemistry confers upon it unique biology, as demonstrated in the dozens of clinical trials employing this distinctive zinc delivery system.