Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model.

Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A.

Proposal for a method of non-restrictive measurement of resting heart rate in a lying position.

Daily monitoring of heart rates is important in health management. Many researchers have analysed heart rate variability by using the resting heart rate because such an analysis can facilitate the early discovery of a variety of illnesses and health conditions. Some problems that arise in measuring heart rate are the feeling of confinement. Therefore, we required a system that could measure the resting heart rate in a static position in such a way that the subject is completely unaware that the measurement is being recorded. We propose a non-restrictive measurement method that uses only an acceleration sensor placed inside a down quilt. This method is easy for home use. The acceleration sensor was placed inside the quilt such that it was positioned opposite to the left-hand side of the subject's chest. Six healthy subjects were requested to lie in the supine position and were covered with the quilt equipped with the acceleration sensor. Mechanical vibrations that resulted from heart activity were carried through the quilt to the acceleration sensor. As a result, periodic vibrations were measured successfully, and in the six subjects, these vibrations were proved to be highly correlated with the R wave of electrocardiograms. The same results were obtained even when the subjects were lying in the left lateral position. The results indicated that our new method, which used an acceleration sensor placed inside a down quilt, was simple and could be used to measure the resting heart rate in a lying position.

Basic Study for Optimal Control of In-Bed Temperature during Sleep.

It is important to create a comfortable environment to restful sleep. In this study, we trial-produced an in-bed temperature control system. At first, we statically controlled the temperature in the subject's bed at 32°C by using the system, and examined how this control affected sleep. We were able to confirm that the ratio of slow-wave sleep (SWS) increased in comparison to cases in which the temperature in the bed was not controlled. Next, the temperature in the subject's bed was dynamically controlled at temperature change patterns according to sleep cycles that is as follows; Heating during the REM sleep period and cooling during the SWS sleep period were conducted n the range of 32±2°C, and the case of the opposite phase. The result showed that cooling during the REM period increased the REM sleep share rate. Based on these results, an increase of the REM sleep share rate at around 30°C could be confirmed, indicating a possibility that the REM period thermoneutrality zone shifted to a lower temperature, compared with that of SWS.

Jogging support system with portable monitoring device and health manage software.

At MEDINFO 2001 we reported about an ambulatory biosignal memory device. As an application of this system, we have developed a portable jogging monitoring device and studied its application for health management here. This device is a micro processor based system with some sensors necessary to monitor condition of the user during jogging, that is, a heart rate sensor, a GPS sensor and a physical activity sensor. We also have developed PC based health management software that receives jogging data after jogging and stores it as a long term jogging trend data. From these long term data it feeds back the distance completion of jogging on the virtual course. Moreover it can show the trend of jogging time, distance, average heart rate and the user can know his/her own health condition.