BBP 212: a biosynthetised Artemisinin derivative

Pritsana Khamchaew, Edwin ten Winkel

BBP 212 is an Artemisinin-like, water-soluble compound synthetised by a genetically engineered yeast with a high yield (up to 120 mg l^-1).

Production of Artimisin out of artemisinic acid by genetically modified yeast (typically Saccheromyces cerevisiae) is not new^1,2, but that usually involves isolation and conversion of artemisinic acid into artemisinin. BBP 212 however is produced directly by a genetically engineered micro-organism.

Further development of this method and testing BBP 212 for it’s antimalarial (typically Plasmodium falciparum) are scheduled.

 

¹Bioengineered Yeast Could Increase Supplies of Potent Malaria Drug
²Synthetic biology extends anti-malaria drug artemisinin's effectiveness

Effect of BBP162 on praeputium eversion of Biomphalaria straminea

Diana Viray, Edwin ten Winkel

The effect of BBP162, a new selective serotonin reuptake inhibitor, on reproductive behaviour on snails was tested on the snail Biomphalaria straminae.

Snails were placed in solutions of BBP162 of ascending strength (2, 5 and 10 μM).

All snails showed praeputium eversion within 10 hours and developed erections. After 72 hours erections started to fade.

MED ≤ 2μM as all snails on the lowest dose showed significant effect.

Ref.:

• G. Nentwig: Another Example of Effects of Pharmaceuticals on Aquatic Invertebrates: Fluoxetine and Ciprofloxacin. In: Pharmaceuticals in the Environment (Ed: Klaus Kümmerer): Pub: Springer Berlin Heidelberg, 2008, Ch. 13
• Fong, Olex, Farrell, Majcharzak, Muschamp: Induction of preputium eversion by peptides, serotonin receptor antagonists, and selective serotonin reuptake inhibitors in Biomphalaria glabrata. Invertebrate Biology. V124, 4. P296-302
• Gust, Buronfosse, Giamberini, Ramil, Mons and Garric: Effects of fluoxetine on the reproduction of two prosobranch mollusks: Potamopyrgus antipodarum and Valvata piscinalis. Environmental Pollution Volume 157, Issue 2, February 2009, Pages 423-429

Effect of Durogesic® (fentanyl patch) compared to BBP 492 (chemically synthetised tetrodoxin derivative) on cancer related pain

Diana Viray, Edwin ten Winkel

BBP492 is a tetrodotoxin like compound that is not identical to any known natural occuring tetrodotoxin compound. In a phase II trial effects of Durogesic® patches on pain in cancerpatients were compared to BBP 492.

Both groups could use oxycodon against 'breakthrough' pain.

On a VAS, patients on BBP492 scored significantly better on pain control than patients on Durogesic® when compared to baseline. Also, patients on BBP 492 had significantly lower need for use of oxycodon during the trial.

 

Durogesic® is a brand name of Janssen-Cilag

Effect of two chemically synthetised tetrodotoxin derivatives (BBP418 and BBP492) in pain therapy.

Diana Viray, Edwin ten Winkel

BBP418 is chemically synthetised but identical to one of the main compounds of tetrodotoxin, the toxin of the pufferfish or blowfish (Tetraodontidae). BBP492 is a tetrodotoxin like compound that is not identical to any known natural occuring tetrodotoxin compound. Both BBP418 and BBP492 are sodium channel blockers, that selectively blocks off the voltage-sensitive sodium channels of excitable tissues and neuronal transmission in skeletal muscles.

In a Phase II trial in 50 cancer patients BBP492 scored significantly higher on improvement of pain on the VAS (visual analogue scale).
Further testing will be done in order to validate these results.

Announcement: BBP153 Sold

NNRTI BBP153 has been sold under a secrecy agreement. As a consequence bbPharma will no longer develop BBP153 in HIV or related conditions.

Edwin ten Winkel, CEO

Effect of BBP 418, a chemically synthetised tetrodotoxin derivative, in pain therapy

Pritsana Khamchaew, Edwin ten Winkel, bbPharma

BBP418 is chemically synthetised but identical to one of the main compounds of tetrodotoxin, the toxin of the pufferfish or blowfish (Tetraodontidae). BBP418 is a sodium channel blocker, that selectively blocks off the voltage-sensitive sodium channels of excitable tissues and neuronal transmission in skeletal muscles. It is being developed as a potent pain-killer and is currently undergoing Phase II trials in 30 patients. Administration of a few microgram appear to be effective in about 75% of subjects.
Tetradotoxin is complex in structure by small molecule standards and contains a guanidinium moiety. The guanidinium ion is able to enter cells via the voltage sensitive Na+ channels, which are critical for cellullar signalling pathways (e.g. transmission of impulses and the mediation of many cell functions). It is likely that this imidazole ring is the part of the molecule that lodges in the channel leaving the rest of the molecule blocking its outer mouth. Their association and dissociation are independent of whether the channel is open or closed. When a neuron (nerve cell) is sending a message, tiny pores or channels in the neuron's membrane open up to let sodium ions enter the cell. Tetrodotoxin (puffer fish toxin) blocks these tiny pores, which in turn prevents any signalling in the nervous system. The result is rapid paralysis and possibly death.
BBP418 differs from other painkillers in that it doesn't have the same side effects as e.g. morphine and its derivatives, there are no known significant interactions with other medicines and is not addictive. It is up to 3,200 times stronger than morphine.
Effects in similar compounds (Tectin®) have shown initial promising but ultimately disappointing effects in the treatment of cancerpatients. BBP418 however is not identical to Tectin® and is believed to hold promise for the treatment of cancerpain as well.

Note: Tetradotoxin is also found in other animals e.g., the California newt and the eastern salamander

Effects of low concentrations of tetradotoxin on rat trigeminal ganglion neurons

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Fuchi Y, Hoashi K, Akaeda H, Makino Y, Noguchi T. Anatomical Distribution and Seasonal Variation of Toxicity of Puffer Fish, "Hoshifugu" Arothron firmamentum specimens collected from the Bungo Channel, Oita. Journal of The Food Hygienic Society of Japan. 39: (6) 421-425 DEC 1998

Lin SJ, Chai TJ, Jeng SS, Hwang DF.Toxicity of the puffer Takifugu rubripes cultured in northern Taiwan.Fisheries Science. 64: (5) 766-770 Oct 1998

Malpezzi ELA, deFreitas JC, Rantin FT. Occurrence of toxins, other than paralysing type, in the skin of tetraodontiformes fish. Toxicon. 35: (1) 57-65 Jan 1997

Matsui T, Taketsugu S, Kodama K, Ishii A, Yamamori K, Shimizu C. Studies on the Toxification of Puffer Fish .1. Production of Tetrodotoxin by the Intestinal Bacteria of a Puffer Fish, Takifugu niphobles. Nippon Suisan Gakkaishi. 55: (12) 2199-2203 Dec 1989

Matsumura K.A. Monoclonal-Antibody Against Tetrodotoxin That Reacts to The Active Group For the Toxicity. European Journal of Pharmacology-Environmental Toxicology and Pharmacology Section.293: (1) 41-45 May 26 1995

Matsumura, K.Tetrodotoxin concentrations in cultured puffer fish, Fugu rubripes. Journal of Agricultural and Food Chemistry. 44: (1) 1-2 Jan 1996

Matsumura K. Production of tetrodotoxin in puffer fish embryos. Environmental Toxicology and Pharmacology.6: (4) 217-219 Dec 1998

Nagashima Y, Hamada Y, Ushio H, Nishio S, Shimakura K, Shiomi K. Subcellular Distribution of Tetrodotoxin in Puffer Fish Liver. Toxicon. 37: (12) 1833-1837 Dec 1999.

Saito T, Noguchi T, Shida Y, Abe T, Hashimoto K. Screening of Tetrodotoxin and Its Derivatives in Puffer-Related Species. Nippon Suisan Gakkaishi. 57: (8) 1573-1577 Aug 1991

Sun K, Wat J, So P. Puffer Fish Poisoning. Anaesthesia and Intensive Care. 22: (3) 307-308 Jun 1994

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Yang C C, Han K C, Lin T J, Tsai W J, Deng J F. An Outbreak of Tetrodotoxin Poisoning Following Gastropod Mollusk Consumption. Human & Experimental Toxicology. 14: (5) 446-450 May 1995

Yu CF, Yu PHF. A Preliminary Study of Puffer Fishes And Their Toxins Found in Hong Kong Waters. Journal of The Food Hygienic Society of Japan 38: (6) 460-463 Dec 1997

Life extending properties of BBP750 in Caenorhabditis elegans

Lam Hoi-ka, E. ten Winkel, bbPharma

Certain drugs such as mianserin have been reported to extend the lifespan in worms by 30%. We have tested BBP750 a serotonin modulator with octopamine inhibiting effects.
Caenorhabditis elegans on BBP750 enhanced diet showed a 25% boost in lifespan compared to C. elegans on a regular diet (bacterial lawn grown on an agar plate, with and without BBP750 enrichment). No Dauer stadia were seen

Interestingly, effects from other studies on BBP750 show that rats have slightly decreased food-intake compared to rats on a regular diet.