Nickolas Mundo

Introduction. The Zika virus (ZIKV) is a Flavavirus that quickly spread across the Americas and Southeast Asia from 2014 to 2016¹. The virus spreads through mosquito vectors, sexual transmission, and transplacentally². Vertical infection of infants can cause microcephaly, hepatitis, ventricularmegaly, and calcification of the cerebrum, while adults can experience Guillain-Barré Syndrome and Myelitis^1,3. The virus encodes ten proteins, 3 structural and 7 non-structural (NS)². These NS proteins have been shown to form complexes (NS1-NS4B and NS2B-NS3), which inhibit the innate immune response⁴. Since no effective vaccine or standard treatment is available for patients, the NS proteins and formation of their complexes are potential novel targets for antiviral therapy^4-8. NS1 has been suggested as a potential antigen for a vaccine against the ZIKV, preventing Antibody-Dependent Enhancement of the ZIKV⁵. Methods. Since formation of NS1-NS4B complexes is critical for viral pathogenicity, investigators have shifted their focus to identifying allosteric and peptide inhibitors capable of blocking or disrupting complex formation. Two such inhibitors, NSC157058 and Bz-Phe(4-CH2NH2)-Arg-B(OH)2, were evaluated for their ability to reduce viral infectivity (allosteric inhibition) and decrease NS2B-NS3 complex catalytic activity (peptide inhibitor), respectively.^6-8 In another approach, investigators generated a set of vaccines by immunizing mice with a combination of four different NS1 segments, spanning the length of the NS1 polypeptide, and tissue plasminogen activator⁵.  Vaccine efficacy was determined by measuring Cytotoxic T Lymphocytes (CTL) killing of infected splenocytes and CD69 upregulation⁵. Moreover, a fluorescent treponemal antibody absorption (FTA) assay determined which portion of NS1 was antigenic⁵. Results. NSC157058 decreased the percentage of ZIKV infected cells in a dose-dependent manner, with 1% infected at a dose of 100 μM⁶. In addition, the peptide inhibitor Bz-Phe(4-CH2NH2)-Arg-B(OH)2 was the most potent peptide tested with an IC50 = 0.11 μM and kt = 0.25 μM ^7,8. The NS1 vaccine stimulated an effective CTL response, with 40% to 60% of splenocytes killed when immunized with polypeptide segments 172-270 and 259-352 of NS1, respectfully. These segments correspondingly increased the T helper cell response, measured by upregulation of CD69⁵. FTA analysis revealed that NS1 polypeptide positions 262-273 activated CTL and positions 202-219 activated Th cells⁵. Conclusion. Both NSC157058 and Bz-Phe(4-CH2NH2)-Arg-B(OH)2 show potential as effective antivirals against the ZIKV through inhibition of NS2B-NS3 complex formation and activity. These compounds can prevent the innate immune response inhibition caused by the ZIKV^6-8. A vaccine utilizing positions 202-219 and 262-273 of NS1 shows promise as an effective vaccine against the ZIKV⁵.

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