5.3.2. Promising Heparan Sulfate Mimicking Molecules

The most promissory HS mimetics that are on clinical trials are: Highly sulfated phosphosulfomannan muparfostat (PI-88) [244], 2,3-*O*-desulfated heparin CX-01 (ODSH) [245], SST0001 [246] and pixatimod (PG545) [214]. The latter was selected from oligosaccharidic HS mimetics of the PG500 series as the best candidate regarding cancer treatment applications [247].

PI-88 is an HPSE inhibitor and also an antagonist of HS-protein interactions. Structurally it is a phospho-mannopentaose obtained through a process of sulfation of a phospho-

mannan complex produced by yeasts [243,248]. It was the first one entering clinical trials and, generally, phase I/II studies demonstrated a satisfactory pharmacodynamic profile of this mimetic that was also considered safe and well-tolerated, showing minor anticoagulant effects. As main results, PI-88 has proven to be a suitable candidate as an adjuvant for postsurgical hepatocellular carcinoma in phase II clinical trials [249,250]. Subsequently, it reached Phase III in clinical trials regarding large series of liver cancer patients after hepatectomy. In fact, it is currently waiting for approval to enter routine clinical use [250]. Patients with advanced melanoma were recruited for a Phase I and Phase III clinical trials and PI-88 activity was beneficial [251]. Overall, PI-88 showed encouraging results for melanoma, multiple myeloma, prostate and lung cancer treatment [205].

CX-01 is a low anticoagulant 2-*O*, 3-*O* desulfated heparin derived from porcine intestinal heparin retaining many anti-inflammatory properties. It has been shown to have a particular potential for acute myeloid leukaemia (AML) treatment [245]. This molecule inhibits leukemic stem cells to concentrate on the bone marrow, therefore enhancing chemotherapy treatments. CX-01 specifically binds chemokine platelet factor 4 (PF4), which is responsible for the negative regulation of megakaryopoiesis [252]. Therefore, by interfering with this process, CX-01 is able to diminish chemotherapy-induced thrombocytopenia. Phase I clinical trial on AML patients demonstrated CX-01 to be well-tolerated and more recently, it entered Phase II and showed promising results in combination with the standard chemotherapy treatment [253].

Preclinical models with SST0001 shown the effective inhibition of myeloma growth in vivo [242]. SST0001 progressed to a Phase I open-label clinical trial design to assess the safety and tolerability profile of this compound in patients with multiple myeloma [254]. Recently, SST0001 was advised for Phase II evaluation [254].

The HS-mimicking molecule with the best clinical evaluation so far is PG545 [255]. PG545 is a fully sulfated glucopyranose tetrasaccharide particularly designed with a hydrophobic 3-cholestanyl group [247,255]. The novel characteristic of this molecule is the stimulation of innate immune cell response to tumours. This stimulation is done via activation of natural killer cells [256]. Clinical trials proved PG545 as a satisfactory alternative in patients with advanced solid malignancies in which standard therapies failed [247]. Currently, PG545 is also being investigated as a potential inhibitor of the SARS-CoV-2 [257].

In addition to the role of HS as an emerging class of molecules for therapeutic strategies, HS glycan chains also constitute important cellular markers. These properties make HS important targets for vaccines development strategies [258].
