Design,synthesis and immunological evaluation of MPLA analogs as adjuvants for RBD-hFc based SARS-CoV-2 vaccine
Objective To investigate the potential of Salmonella minnesota monophosphoryl lipid A(MPLA)as adjuvants for RBD-hFc based SARS-CoV-2 vaccine and the influence of functional group at C-1 and C-6'position,herein,a series of MPLA derivatives were designed and synthesized.Methods The target com-pounds were synthesized using the commercially available glucosamine as a starting material through a series of reactions,including glycosylation,condensation,phosphorylation,hydrogenation and so on.The adjuvant activities of compounds 1-5 were evaluated by mixing with a subunit vaccine candidate RBD-hFc protein through mouse immunization on day 0 and day 14 with the clinically alum adjuvant as the positive control.Each mouse was bled on days 14,28 and 42 post-first immunization,the immunological activity was evalua-ted through the determination of IgG titer and IgG isotype,the ability of antisera to inhibit the RBD protein binding to ACE2 and neutralizing antibody level.Results Five MPLA derivatives were synthesized,and the structures of the target compounds and intermediates were characterized by NMR spectra and HRMS.The immunological evaluation showed that compound 1 exhibited better adjuvant activity than Al,and the adju-vant activities of compounds 3 and 4 were comparable to A1.Conclusion MPLA derivatives have the poten-tial to be adjuvants for the development of RBD-hFc based SARS-CoV-2 vaccine.Preliminary structure-ac-tivity relationship analysis of MPLA analogs shows that the functional groups at C-1 or C-6'positions affect the biological activity.The replacement of the hydroxy group at C-1 position by methoxy or amino group will decrease the activity,however,the hydroxy group at C-6'position replaced by amino group can increase the activity.
MPLA derivativesadjuvantRBD-hFcrecombinant protein vaccine of SARS-CoV-2
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