ABSTRACT
We are utilizing molecular technology to isolate a family of parasite-encoded genes for proteins likely to differ functionally and, by inference, structurally from host cells. Such proteins are likely to be attractive targets for chemotherapeutic attack. The majority of malarial genes characterized to date code for ‘antigens’ that have been isolated by screening expression libraries with hyperimmune sera in the pursuit of candidates for vaccines (Kemp et al., 1986). None of these gene products has clearly established functions within the parasite. Of the ‘housekeeping’ genes that have been isolated from Plasmodium falciparum and sequenced, most share at least 50 per cent of their derived amino acid sequence with the equivalent mammalian protein (see Table 37.1) (Weber, 1988). The one parasite protein known to be a useful drug target, the product of the dihydrofolate reductase-thymidylate synthetase (DHFR-TS) gene complex, has much less similarity in the susceptible moiety (DHFR, <30 per cent), which is the site of action of pyrimethamine and proguanil (Walter, 1986). Resistance to these drugs has emerged and elegant work comparing the derived amino acid sequences of the DHFR-TS gene complex between sensitive and resistant strains has demonstrated altered amino acid residues at the substrate binding site (Bzik et al., 1987; Peterson et al., 1988; Cowman et al., 1988; Snewin et al., 1989; Foote et al., 1990; Peterson et al., 1990).
