## 8 cAMP Signaling in the Kinetoplasids: Small GTPases Control Host Cell Invasion  
Despite recent advances in drug research, finding a safe, effective, and easy to use chemotherapy for HAT caused by _Trypanosoma_ ssp. still remains a challenging task [97]. Pentamidine and surname can be administered only in the first stage of infection of HAT. The second stage drugs melansoprolol and edimithine have disadvantages of their own. Melarsoprolol is toxic causing encephalopathy, and edimithine is laborious to administer and lacks efficacy against _T. brucei rhodesiene_ (East African Sleeping sickness). There might be an an opportunity in targeting downstream effectors of a cAMP-signaling pathway with remarkable features in trypanosomes. Although there is inadequacy of current treatments which should rather speed up drug development, new drugs have been slow to emerge. The importance of cAMP as a second messenger molecule in trypanosomes is reflected by the high number of genome-encoded adenylate cyclases (ACs) with more than 80 genes and pseudogenes. The first adenylate cyclase X-ray structure was obtained from _Trypanosoma brucei_ causing African trypanosomiasis [98]. This AC belongs to the type II class of ACs which exclusively occur in protozoa. They contain an extracellular domain, for putative receptor binding, a single transmembrane domain span, and a cytosolic, catalytic region. ACs are structurally different in comparison to their mammalian counterparts. While the mammalian protein has 12 transmembrane domains, _Trypanosoma brucei_ has only one. However, the basic catalytic mechanism seems to be conserved between them. Trypanosomes possess ACs with a variable large extracellular N-terminal domain and an insertion in the G-protein-binding domain although G-proteins are absent. However, the ligands binding to the N-terminal domain remain to be identified. To date, no experimental report for an AC from _Trypanosoma cruzi_ has been published. In their genome, trypanosomes contain multiple expression sites (ESs) for a highly variable surface glycoprotein (VSG) to evade the host immune response. Downstream of the ESs, a set of genes called expression site-associated genes (ESAGs) are cotranscribed. These genes modulate the host innate immune response [99]. It was shown by RNAi that the small GTPase Rap-1 controls VSG expression in blood stream forms (BF) and at the insect stage (procyclic form) [100]. Targeting these genes which are highly expressed in the blood stream form might be a powerful tool for drug discovery. Collectively, it is now evident that instead of cAMP the products of cAMP hydrolysis are responsible for differentiation in trypanosomes [101]. This does not rule out the involvement of canonical cAMP signaling components like ACs since they may be necessary for initial cAMP production. There are four groups of cAMP-dependent phosphodiesterase in trypanosomes. Each group has one or two representatives. Most of them are structurally similar to human PDEs. The first crystal structure of phosphodiesterase B1 (PDEB1) was obtained from _Trypanosoma brucei_[102]. The structure confirmed the presence of a parasite-specific pocket between amino acid residues Gln874 and Tyr845 and is absent in the human orthologue. This property has been shown to be useful for the design of specific lead structures and inhibitors. In human PDEs the pocket is gated by two large residues while smaller residues are found in the parasite orthologue. These findings resulted in an approach of targeting the P-pocket with hPDE inhibitors developing more specificity for the parasitic enzyme on the basis of fragment growing [103]. The resulting catechol pyrazolines act as potent TbrPDEB1 inhibitors with IC\({}_{50}\) values down to 49 nM. The compounds also block parasite proliferation. Knockdown experiments of PDEB1 and PDEB2 in mouse models provided clues that PDEs are necessary for motility and virulence [104]. During infection, _Leishmania_ parasites arrest in phagolysosomes in the host cell to avoid transport to the lysosomes.