Malaria parasites have their Achilles' heel; they are vulnerable in small parts of their relevant molecules where they can be wounded and killed.These are sporozoite and merozoite protein conserved high activity binding peptides (cHABPs), playing a critical role in binding to and invasion of host cells (hepatocytes and erythrocytes, respectively).cHABPs can be modified by specific amino acid replacement, according to previously published physicochemical rules, to produce analogues (mHABPs) having left-handed polyproline II (PPIIL)-like structures which can modulate an immune response due to fitting perfectly into the HLA-DRβ1* peptide binding region (PBR) and having an appropriate presentation to the T-cell receptor (TCR). Achilles' heel of microbesAccording to the historian Statius, the Nereid Thetis, Achilles' mother dipped him headfirst into the River Styx when he was born to make him immortal and so that no arrow could wound him; not having anywhere else to hold him by, she held him by his right heel, this therefore becoming the only vulnerable site for the hero of the Iliad.Microbes also have their Achilles' heel, particularly the parasite P. falciparum, the causal agent of the lethal form of malaria; the conserved high activity binding peptides (cHABPs) from sporozoite (Spz) and merozoite (Mrz) proteins directly participate in binding to and invasion of host cells (hepatocytes and erythrocytes, respectively) (Garcia et al., 2006;Rodriguez et al., 2008).These conserved functionally relevant sequences, common to all the parasite's genetic variants in the world, are highly vulnerable to blocking parasite cell binding, cell lysis and death.When properly modified, these structures become mHABPs (Patarroyo and Patarroyo, 2008;Curtidor et al., 2011;Patarroyo et al., 2011) containing segments similar to native protein structures while some other portions, modified according to previously demonstrated physicochemical rules, allow their fit into the HLA-DRβ1* peptide binding region (PBR), converting mHABPs into strain-transcending, immune protection-inducing structures (IMPIPS).IMPIPS induce very high, strong, specific antibody and protective immune responses, as has been thoroughly demonstrated, establishing a new methodology for vaccine development.These cHABPs are thus the Achilles' heel of microbes, particularly the malaria parasite.The malaria parasite's Achilles' heel revealed by 3D structural analysis Analysing the Spz proteins studied CSP region I cHABP 4383 contains the RxLxE Plasmodium falciparum export element (PEXEL) motif (shadowed) (Table 1) (Hiss et al., 2008) mediating parasite protein membrane transport and Kappa B factor activation to induce Spz differentiation into Mrz.CSP 4388 (Table 1), considered to link repeats region to RII was localized 15 residues upstream the high content heparan sulphate proteoglycan (HSPG) binding site on hepatocytes where the parasite will become arrested and reproduce (Mota et al., 2001;Sibley, 2004).This CSP region I 3D structure has not yet been determined, therefore, these cHABP localizations are not shown in Figure 1.However, the 3D structure for the C-terminal CSP region III (named the α thrombospondin related (TSR) domain containing highly polymorphic T-helper epitopes Th2R, Th3R and CS.T3 has recently been determined by X-ray crystallography (Doud et al., 2012), an unexpected folding being found where the N and C termini are extremely close to each other.Intermediate conserved binding capacity peptide 4397 (Figure 1A, Table 1) in the β1 strand of this structure establishes a network of Hbonds between 323 I and 333 P with 319 Y from 4394, 324 Q with 355 K, 328 S with 346 I, in non-binding 4400 and 4398 peptides respectively, and 341 G with 369 C in highly variable nonbinding sequence 4403 (J.E. Suarez et al., 2001).The CS.T3 conserved region associated with CD4* T-cell response in our 4405 peptide does not bind to hepatocytes.Sporozoite TRAP cHABP 3243 (Table 1) plays a main role in cell entry, cHABP 3271 (Table 1) contains the residues forming the metal ion-dependent adhesion site (MIDAS, highlighted) and 3279 (Figure 1B) which is the HSPG binding site located in the vWA domain (Pihlajamaa et al., 2013).It was also seen that bridges are formed between intermediate binding peptide 3277 (Figure 1B) amino acids 201 F, 202 L, 203 V and 205 C with 197 A, 198 F, 199 N and 200 R (Figure 1B).Similarly, cHABP 3287 (Figure 1C) located in the TSR region formed by one ripped and two anti-parallel and β-strands forms a groove conformed by π cation interactions between 247 W, 250 W and 262 R, 264 R (respectively), plus 3 H-bonds established between cHABP 3289 243 S, 248 D and 251 S with 266 R, 263 S and 264 R (Figure 1C).Positively-charged residues from this structure bind to negatively-charged receptors like heparan sulphate proteoglycans (HSPG) from hepatocytes and endothelial cells (Tossavainen et al., 2006) for mediating cell traversal a c t i v i t y a n d i n v a s i o n .M e a n w h i l e , T R A P 3 3 4 7 ( 541 YAGEPAPFVEPLGEE 555 ) located 15 residues upstream the aldolase binding site, mediates this protein's binding to