Monomeric griffithsin tandemers
Inventors
O'Keefe, Barry R. • Wlodawer, Alexander • Moulaei, Tinoush
Assignees
US Department of Health and Human Services
Publication Number
US-9982025-B2
Publication Date
2018-05-29
Expiration Date
2034-06-05
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Abstract
The invention provides a construct containing two or more monomeric griffithsin molecules, optionally joined by a linker, as well as conjugate comprising the construct, a nucleic acid encoding the construct or conjugate, vectors, and cells. A nucleic acid encoding the polypeptide or fusion protein, as well as compositions or cells comprising the polypeptide, fusion protein, or nucleic acid also are provided.
Core Innovation
The invention provides constructs containing two or more monomeric griffithsin (mGRFT) molecules, optionally joined by a linker, as well as conjugates comprising these constructs. It also includes nucleic acid molecules encoding the constructs or conjugates, vectors, cells containing these nucleic acids or vectors, and compositions comprising these components. These constructs can inhibit viral infections by targeting viral glycoproteins.
The problem addressed is the need for additional forms of griffithsin with improved potency. The background outlines that viruses such as HIV protect themselves using glycan shields on their surface glycoproteins, making them difficult targets for neutralizing agents. While native dimeric griffithsin (GRFT) shows potent antiviral activity, monomeric griffithsin (mGRFT) exhibits significantly lower anti-HIV activity. There remains a need for griffithsin forms that improve upon the potency limitations of existing monomeric or dimeric forms.
Claims Coverage
The patent contains one independent claim focusing on the construct of multiple monomeric griffithsin molecules joined by a specific linker and its variations.
Construct of multiple monomeric griffithsin molecules joined by a specific (Gly-Thr-Gly)n linker
A construct comprising two or more monomeric griffithsin molecules joined by a linker of the form (Gly-Thr-Gly)n, where n is from 1 to 5, with at least one monomeric griffithsin molecule comprising an insertion of two or more residues between Ser16 and Gly17.
Constructs containing three or four monomeric griffithsin molecules
Constructs specifically containing three or four monomeric griffithsin molecules joined via the above linker.
Insertion of residues including a serine between Ser16 and Gly17 in monomeric griffithsin
The inserted residues between Ser16 and Gly17 in the monomeric griffithsin can include serine, with preferred sequences being (Gly-Ser)n where n is 1 or 2.
Nucleic acid encoded constructs and specific sequences
Constructs encoded by specific nucleic acid sequences (SEQ ID NO: 6 for monomeric griffithsin and SEQ ID NO: 8, 10, 12, or 14 for constructs) and comprising specific amino acid sequences (SEQ ID NO: 9, 11, 13, or 15).
Conjugates comprising the constructs with effector components
Conjugates comprising the construct and at least one effector component selected from polyethylene glycol, albumin, dextran, toxins, immunological reagents, viruses, viral envelope glycoproteins, antiviral agents, or solid support matrices.
Compositions comprising the constructs, conjugates, nucleic acid molecules, vectors, or cells and carriers
Pharmaceutical or other compositions comprising the constructs, conjugates, nucleic acid molecules encoding the construct, recombinant vectors, or cells comprising such nucleic acids or vectors, together with a carrier.
Methods of prophylactically or therapeutically inhibiting viral infections
Methods for inhibiting viral infections, particularly HIV infections, by administering the constructs or compositions thereof to cells or hosts.
Use of the constructs for virus inactivation on biological samples or inanimate objects
Methods of inhibiting viruses in biological samples or on inanimate objects by contacting them with viral-inhibiting amounts of the constructs or compositions, optionally along with other antiviral agents.
The independent claims cover constructs of two or more monomeric griffithsin molecules linked via (Gly-Thr-Gly)n linkers with specified residue insertions, nucleic acid encoding these constructs, conjugates with various effector components, pharmaceutical compositions, and therapeutic or prophylactic treatment methods targeting viral infections, especially HIV.
Stated Advantages
The monomeric griffithsin tandemers exhibit significantly improved anti-HIV activity compared to monomeric griffithsin, showing 5- to 10-fold better potency than native dimeric griffithsin.
The constructs provide potent antiviral agents that do not cause virion aggregation, which is beneficial in avoiding unwanted agglutination effects while maintaining high potency.
Flexible linkers in the constructs enable enhanced binding to glycan ligands on viral envelope glycoproteins, potentially increasing the effectiveness of viral neutralization.
The constructs and conjugates can be produced recombinantly or by chemical synthesis, allowing scalable and versatile production methods.
The constructs bind to viral envelope glycoproteins with high affinity and can be adapted for diverse therapeutic and prophylactic applications, including formulations suitable for topical, oral, parenteral, and inanimate object sterilization use.
Documented Applications
Inhibition of viral infections, specifically HIV (including HIV-1 and HIV-2, multiple clades and subtypes).
Therapeutic or prophylactic treatment of hosts to prevent or treat viral infections using the inventive constructs or compositions.
Use as antiviral agents against a broad range of enveloped viruses such as influenza viruses, coronaviruses (including SARS), hepatitis C virus, Ebola, and herpes viruses.
Formulations for topical application, including intravaginal administration for female-controllable prophylaxis against HIV.
Use in virucidal sterilization of inanimate objects such as medical equipment, laboratory supplies, and contraceptive devices.
Use of genetically engineered cells or organisms expressing the constructs for sustained in vivo delivery of antiviral agents.
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