Piotr Graczyk

Caspase inhibitors as anti-inflammatory and antiapoptotic agents.

The striking efficacy of Z-VAD-fmk in the various animal models presented above may reflect its ability to inhibit multiple enzymes including caspases. In accord with this, more selective, reversible inhibitors usually show low efficacy in multifactorial models such as ischaemia, but may offer some protection against NMDA-induced excitotoxicity and hepatitis. Importantly, caspase inhibitors may exhibit significant activity in vivo even when they are applied post insult. As far as the CNS is concerned, the first systemically active inhibitors have emerged. Functional recovery could be achieved in some ischaemia models, but long-term protection by caspase inhibitors is still being questioned. Recent developments in drug design enabled the first caspase inhibitors to enter the clinic. Although initially directed towards peripheral indications such as rheumatoid arthritis, caspase inhibitors will no doubt eventually be used to target CNS disorders. For this purpose the peptidic character of current inhibitors will have to be further reduced. Small molecule, nonpeptidic caspase inhibitors, which have appeared recently, indicate that this goal can be accomplished. Unfortunately, many fundamental questions still remain to be addressed. In particular, the necessary spectrum of inhibitory activity required to achieve the desired effect needs to be determined. There is also a safety aspect associated with prolonged administration. Therefore, the next therapeutic areas for broader-range caspase inhibitors are likely to involve acute treatment. Recent results with synergistic effects between MK-801 and caspase inhibitors in ischaemia suggest that caspase inhibitors may need to be used in conjunction with other drugs. It can be expected that, in the near future, research on caspases and their inhibitors will remain a rapidly developing area of biology and medicinal chemistry. More time, however, may be needed for the first caspase inhibitors to appear on the market.

Lee Rubin: Our mentor and role model.

In her News Feature “Out of bounds” (27 January p. [339][1]), A. McCook strove to present an objective narrative of the situation in which a student at Harvard University was forced to undergo a psychiatric evaluation and then filed a court order against scientist Dr. Lee Rubin. However, McCook failed to take into consideration Rubins longstanding reputation as a scientist and a mentor. We are scientists who have worked with, been mentored by, or collaborated with Rubin. Some are current members of his laboratory, some have known him for many years, and a few have known him for more than 30 years. We could not let this story stand without adding our perspective. Rubins scientific reputation can be readily appreciated simply by skimming through the list of his stellar publications. However, a dry bibliography fails to illuminate the quality of the scientist behind the science. Rubin has always upheld the highest standards of scientific and personal integrity. His kindness and concern for the personal well-being and professional development of his graduate students, and indeed everyone in his laboratory, has always been clearly evident. Rubin has always had our backs, whether as a mentor, a colleague, a boss, or a friend. He upholds the highest standards of scientific rigor while providing compassionate mentorship. His commitment to leading by example means we place the highest value on our friendship and connections with him. We have sought out his scientific counsel and, in several cases, engaged in collaborations that span many years. We feel fortunate to have had the opportunity to know and to work with him. It is our collective experience that besides being an outstanding scientist, he is a warm and caring scientific mentor who does not deserve to have the reputation he has built over 40 years or more besmirched. [1]: /lookup/doi/10.1126/science.355.6323.339