Severe and cerebral malaria kill about 2-3 million or more people per year 90 % are young children. There is no preventive vaccine, and the malaria parasites are increasingly resistant to anti-malarial drugs. The initial infective process of the malaria parasite in humans is between the invading parasite and hepatocytes of the host. In several studies, the heparin/heparan sulfate (H/HS) receptor systems have been implicated in this invasion. We previously applied our combinatorial family of heparin-mimetic S-oligoS (See HD 001315-14,16) to characterize their in vitro inhibition capacities against malaria parasites in vitro and revealed that the heparin-based inhibition of P. yoelii sporozoite (freshly isolated from infected mosquitoes) invasion of hepatocytes was governed by a degree of structural specificity and was concentration dependent. Two highly active library components (Cp) were identified, Cp6 and 11, with estimated EC 50s of 3.5 and 5 micromolar, resp;Cp11 had earlier displayed negligible heparin-anticoagulant capacity against thrombin (which occasionally causes bleeding when pharmaceutical heparin is administered clinically). Inhibitory Capacity Further studies of the inhibitory capacities of Cp11 and 6 against liver stage development of malaria parasites in vitro are planned. Our renewed mutual Confidentiality Agreement with Bene Arzneimittel, Munich, D.R. has provided another large lot of heparin-mimetic pharmaceutical starting material for preparation of additional Cp11 as well as our HIV-1 inhibitors, SOLIS and the Cp 8 group. Development of an enlarged investigative preparation of Cp11 is ongoing to insure adequate fractionation results and agreement between the two batches (See 1 ZIA HD001315-16 DIR). Structural Study We found by spectroscopic and chemical analyses that the H/HS-mimetic S-OligoS Cps besides carrying sulfate groups on up to 85 percent of the sugar hydroxyls (high anionic density) also contain a specific tetrasaccharide motif of three 1-4 beta linked xyloses and a 1-2 alpha-linked glucuronic acid, one third or less O methylated (as a branch on the xylan chain). In addition, the number of these alternate forms appears to increase with increase in mass of the Cp. Alternate forms induce specific distance and angle alterations in the otherwise uniform S-OligoS chain properties. Such a motif could accommodate the subtle specific variations in geometries involving sulfates that are required for mutifunctional mimicry of the heparins. Further elucidation of the Cp11 structure might enable application of advanced high throughput methods in further drug development. Cp11 and 6 samples are in progress for current study by FTIR and NMR analyses. Cerebral Malaria We anticipate testing our H/HS-mimetic combinatorial family for a potential agent against the acute cerebral distress and fatality in patients with cerebral malaria as soon as collaboration with a malarial parasitologist is arranged. """"""""Copathogenesis"""""""" Recently developed statistical analysis was used by clinicians to calculate findings (Science 319:1603 2006) that HIV infection in malaria endemic regions is spread at a rate 8 percent higher than in other regions where HIV-AIDS is on the rise due to an unexplained vulnerability of either patient to the second pathogen. We had suggested previously that co-treatment of malaria and HIV-AIDS would be feasible because of the close similarity in the physicochemical properties of the respective S-oligoS inhibitors. Our preliminary in vitro study on combined dosing of Cp11 and SOLIS (S-OligoS malaria parasite and HIV-1 inhibitors, resp.) confirmed the compatibility of the two potential drugs in assays using CM-SS cells. Given the complexity of the known or novel biological systems which may be involved, the data are currently interpreted based on several biological models to generate appropriately designed assays which will be used with the Cp11 to elucidate this """"""""copathogenesis"""""""".
