Synthetic compounds comprising dihydroisoquinolinone monomers

Abstract

Embodiments are directed to dihydroisoquinolinone (Dhq) monomers and synthetic compounds comprises at least Dhq monomer having the structure (I). In such embodiments, X is selected from C and N and each R1 and R2 are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof. In some embodiments, the synthetic compounds can bind to a spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to fentanyl.

Description

S1647.188.111 (SRI-230078-PCT) SYNTHETIC COMPOUNDS COMPRISING DIHYDROISOQUINOLINONE MONOMERS GOVERNMENT RIGHTS

[0001] This invention was made with Government support under contract no. N66001- 14-C-4059 awarded by the Space and Naval Warfare Systems Command Systems Center Pacific. The Government has certain rights in this invention. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing (S164718811_SequenceListing.xml; Size: 30,868 bytes; and Date of Creation: September 16, 2024) is herein incorporated by reference in its entirety. BACKGROUND

[0003] Various biological polymers, including antibodies, proteins, peptides, and nucleic acids, can be used as affinity reagents for a wide range of applications, including therapeutics, diagnostics, detection, biotechnology, analytical reagents, and catalysts, among other applications. These affinity reagents can possess remarkable properties, such as potency, target selectivity, and biological activity. However, the biological polymers are limited to natural building blocks or closely related building blocks and can suffer from limitations in terms of stability, structure, and function, among other limitations. SUMMARY

[0004] The present invention is directed to synthetic compounds comprising at least one dihydroisoquinolinone (Dhq) monomer, and which can include synthetic polymers.

[0005] Various aspects of the present disclosure are directed to a synthetic compound comprising at least one Dhq monomer having a structure of:,S1647.188.111 (SRI-230078-PCT) wherein: X is selected from C and N; and each R1and R2are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof, wherein the compound is selected from: d(Glu)-DhqO-Phe(4F)-phenyl-acetamido-methylene (PAM)-d(Ala)-DhqY- Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE- Ala-PAM-DhqF-d(Lys)-Val-PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- PEG12-Gln(PEG-Biotin)-CONH2; Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin)-CONH2; d(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM; Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM; PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala)-PEG12-Gln(PEG-Biotin); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin);S1647.188.111 (SRI-230078-PCT) d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-(L)Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Cys(alph-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12-Cys(alpha-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12; Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM- PEG12-Gln(PEG-Biotin); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)-Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)- Phe(4F)-PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM;S1647.188.111 (SRI-230078-PCT) DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM; DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM-d(Lys)- DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY-d(Glu)- Phe-PAM-DhqE-Gly-Phe(4F)-PAM; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(-Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM;S1647.188.111 (SRI-230078-PCT) d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val- PAM-DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqE-Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala-DhqE-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM- Ala-DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)- DhqY-Ala(Cp)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)- DhqO-Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)- CONH2; d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2;S1647.188.111 (SRI-230078-PCT) d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; and d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2.

[0006] In some aspects, the at least one Dhq monomer includes:.

[0007] In some aspects, the synthetic compound is configured to bind to a spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to fentanyl.

[0008] In some aspects, DhqB, DhqE, DhqF, DhqO, and DhqY include:

[0009] In some aspects, Ala(Cp), Phe(4F), and Ser(OMe) include:S1647.188.111 (SRI-230078-PCT) NH NH(Fmoc-Ala(Cp)), (Fmoc-Phe(4F)), and NH(Fmoc-Ser(OMe)).

[0010] Various aspects of the present disclosure are directed to a synthetic compound comprising at least one Dhq monomer, wherein the compound is selected from: d(Glu)-DhqO-Phe(4F)-phenyl-acetamido-methylene (PAM)-d(Ala)-DhqY- Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE- Ala-PAM-DhqF-d(Lys)-Val-PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- PEG12-Gln(PEG-Biotin)-CONH2; Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin)-CONH2; d(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM; Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM; PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala)-PEG12-Gln(PEG-Biotin);S1647.188.111 (SRI-230078-PCT) d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-(L)Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Cys(alph-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12-Cys(alpha-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12; and Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM- PEG12-Gln(PEG-Biotin).

[0011] In some aspects, DhqB, DhqE, DhqF, DhqO, and DhqY include:

[0012] In some aspects, Ala(Cp), Phe(4F), and Ser(OMe) include:S1647.188.111 (SRI-230078-PCT) NH NH(Fmoc-Ala(Cp)),(Fmoc-Phe(4F)), and NH(Fmoc-Ser(OMe)).

[0013] In some aspects, the synthetic compound is configured to bind to a spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0014] Various aspects of the present disclosure are directed to a synthetic compound comprising a plurality of dihydroisoquinolinone (Dhq) monomers having a structure of:wherein: X is selected from C and N; and each R1 and R2 are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof; a plurality of amino acid monomers selected from: l-α-amino acids, d-α-amino acids, and non-natural amino acids of Ala(Cp), Phe(4F), Ser(OMe); and cleavable groups between at least portions of the plurality of Dhq monomers and the plurality of amino acid monomers, wherein the synthetic compound is configured to bind to fentanyl.

[0015] In some aspects, each of the plurality of Dhq monomers have a structure of:.

[0016] In some aspects, the synthetic compound includes a plurality of molecules, each of the plurality of molecules including a subset of the plurality of Dhq monomers andS1647.188.111 (SRI-230078-PCT) the plurality of amino acid monomers, and the cleavable groups between each of the plurality of molecules.

[0017] In some aspects, the synthetic compound includes eight molecules, each of the eight molecules including three monomers including one of the plurality of Dhq monomers and two of the plurality of the amino acid monomers, and one of the cleavable groups coupled to one of the three monomers.

[0018] In some aspects, the plurality of amino acid monomers are selected from l-α- amino acids, d-α-amino acids, and non-natural amino acids including: Ala(Cp), Phe(4F), Ser(OMe), Ala, Gly, Phe, Val, d(Ala), d(Gly), d(Glu), and d(Lys).

[0019] In some aspects, each R1and R2are independently selected from H, phenol, O- allyl, and (CH2)2-COO-allyl.

[0020] In some aspects, R1 includes:

[0021] In some aspects, R2includes:.

[0022] In some aspects, each of the plurality of Dhq monomers includes a structure selected from:S1647.188.111 (SRI-230078-PCT)

[0023] In some aspects, each of the plurality of Dhq monomers includes a structure selected from:

[0024] In some aspects, the synthetic compound includes: d(Glu)-DhqB-Ala-phenyl-acetamido-methylene (PAM)-d(Glu)-DhqB- Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)-PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)- Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly- PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM;S1647.188.111 (SRI-230078-PCT) DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)- Phe(4F)-PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM; DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM-d(Lys)- DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY-d(Glu)- Phe-PAM-DhqE-Gly-Phe(4F)-PAM; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(-Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM;S1647.188.111 (SRI-230078-PCT) DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val- PAM-DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqE-Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala-DhqE-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM- Ala-DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)- DhqY-Ala(Cp)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2;S1647.188.111 (SRI-230078-PCT) d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)- DhqO-Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)- CONH2; d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; and d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2, wherein DhqB, DhqE, DhqF, DhqO, and DhqY include five different Dhq monomers, each having the structure.

[0025] In some aspects, DhqB, DhqE, DhqF, DhqO, and DhqY include:S1647.188.111 (SRI-230078-PCT)

[0026] In some aspects, Ala(Cp), Phe(4F), and Ser(OMe) include: NH NH(Fmoc-Ala(Cp)), (Fmoc-Phe(4F)), and Fmoc-NH O C MeO OH (Fmoc-Ser(OMe)). BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0028] Various example embodiments can be more completely understood in consideration of the following detailed description in connection with the accompanying drawings, in which:

[0029] FIGs.1A-1C illustrate example synthesis and characterization of dihydroisoquinolinone (Dhq) monomers, in accordance with the present disclosure.

[0030] FIGs.2A-2D illustrate the design of a compound library, in accordance with the present disclosure.

[0031] FIGs.3A-3E illustrate the preliminary structure activity relationship (SAR) data for compound 1, in accordance with the present disclosure.

[0032] FIGs.4A-4C illustrate data on the stability and selectivity of compound 1, in accordance with the present disclosure.S1647.188.111 (SRI-230078-PCT)

[0033] FIGs.5A-5D illustrate data characterizing compound 1 binding interaction with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor binding domain, in accordance with the present disclosure.

[0034] FIGs.6A-6B illustrate compound affinity to SARS-CoV-2 spike receptor binding domain in mice, in accordance with the present disclosure.

[0035] FIG.7 illustrates data characterizing compound binding interaction with the SARS-CoV-2 spike receptor binding domain, in accordance with the present disclosure.

[0036] FIGs.8A-8D data characterizing compound binding interaction with fentanyl, in accordance with the present disclosure.

[0037] FIG.9 is a table showing the physiochemical properties of biologically-active polymers as compared to the Dhq monomers, in accordance with the present disclosure.

[0038] FIGs.10A-10B show the results for assessing selectivity in cells expressing spike protein, in accordance with the present disclosure.

[0039] FIG.11 is a graph of the melting curve plot for compound 1, in accordance with the present disclosure. DETAILED DESCRIPTION

[0040] In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific examples in which the disclosure can be practiced. It is to be understood that other examples can be utilized, and various changes may be made without departing from the scope of the disclosure. The following detailed description, therefore, is not to be taken in a limiting sense, and the scope of the disclosure is defined by the appended claims. It is to be understood that features of the various examples described herein may be combined, in part or whole, with each other, unless specifically noted otherwise.

[0041] Embodiments in accordance with the present disclosure are directed to synthetic compounds which are formed of dihydroisoquinolinone (Dhq) and amino acid building blocks for a variety of purposes, including as affinity reagents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and / or fentanyl. As noted above, prior approaches for development of biological polymers include the use of natural building blocks or closely related ones, such as amino acids and nucleic acids. In many instances, functionality of the biological polymer is identified by screening. For example, methods such as peptide phase display, messenger ribonucleic acid (mRNA) display, one-bead-one compound peptide libraries, aptamer screen, and antibodyS1647.188.111 (SRI-230078-PCT) development can be used. Such methods rely on the chemical modalities with the building blocks being limited to the natural building blocks or scaffolds with minor non- natural modifications during the screening and discovery process. Only after identifying biological polymers in the screening process as potential affinity reagents, non-natural modification can be incorporated, albeit with certain limitations. Presently, there is no or limited technology available for the high-throughput screening of synthetic polymers and other compounds with a vast array of building blocks suitable for various applications. Hence, a vast chemical space of synthetic compounds remains missed. By using Dhq building blocks, embodiments of the present disclosure are directed to sequence-controlled synthetic compounds (e.g., synthetic polymers) which can be affinity reagents for a variety of applications and which expands the available chemical spaces. The compounds can have superior properties, including stability, potency, and / or selectivity, among others.

[0042] In some embodiments, synthetic compounds of the present disclosure are synthetic polymers formed of a plurality of molecules coupled together by cleavable groups, with each molecule including a plurality of monomers including at least one Dhq monomer and amino acid monomer. Such synthetic polymers may be referred to as “Techneins® compounds” as further described herein. The Techneins® compounds disclosed herein are novel molecules which can be formed using at least some of same features and attributes as described in: US Publication No.2021 / 0065848, published on March 4, 2021 and titled “Mass Spectrometry Distinguishable Synthetic Compounds, Libraries, and Methods Thereof”; US Publication No.2021 / 0208157, published on July 8, 2021 and titled “Affinity Reagent and Catalyst Discovery Though Fiber-Optic Array Scanning Technology”; US Publication No.2023 / 0393140, published on December 7, 2023 and titled, “Binding Assays Involving a Plurality of Synthetic Compounds, Targets, and Counter Targets; and PCT Publication No. WO2023 / 240050, published on December 14, 2023 and titled “Antibody Repurposing”, which are each incorporated herein by reference in their entireties for their teachings.

[0043] Non-natural monomers used as building blocks in such compounds can have chemical accessibility and physiochemical properties that may influence three- dimensional (3D) intra- and inter-molecular interactions within the compounds, ease of synthesis and scalability, functional diversity, chiral rigidity to promote local secondary structure, and / or conformation flexibility to allow for folding and inducible binding. Embodiments of the present disclosure are directed to Dhq monomers and / or syntheticS1647.188.111 (SRI-230078-PCT) compounds having at least one Dhq monomer. The Dhq monomers are integrated into a synthetic compound library, which can be employed in multiple screens against a panel of target molecules or other substances and to yield potent synthetic affinity reagents. The synthetic compound library formed using the Dhq monomers significantly expands the chemical space as compared to libraries that use natural building blocks. In some embodiments, the synthetic compounds include affinity reagents to different targets with superior properties, as described above.

[0044] Disclosed herein are Dhq monomer(s) comprising:wherein X is selected from C and N, and each R1and R2are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof.

[0045] In some embodiments, the Dhq monomer includes the structure of:.

[0046] In some embodiments, each R1 and R2 are independently selected from H, phenol, O-allyl, and (CH2)2-COO-allyl.

[0047] In some embodiments, R1includes:

[0048] In some embodiments, R2 includes:

[0049] In some embodiments, the Dhq monomer is selected from:S1647.188.111 (SRI-230078-PCT)well as derivatives thereof.

[0050] In some embodiments, the Dhq monomer is selected from:derivatives thereof. The above monomer structures include the (-)S, S and (+)R, R enantiomers, as further illustrated by FIG.1B. Unless noted otherwise, the DhqS1647.188.111 (SRI-230078-PCT) monomers in the synthetic compounds described herein include (-)S, S enantiomers. A (+)R, R enantiomer is denoted in a synthetic compound as (+)Dhq, such “(+)DhqE”.

[0051] Various embodiments are directed to a synthetic compound, e.g., a synthetic polymer, comprising at least one Dhq monomer having the structure of:wherein X is selected from C and N, and each R1and R2are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof.

[0052] In some embodiments, each R1 and R2 are independently selected from H, phenol, O-allyl, and (CH2)2-COO-allyl.

[0053] In some embodiments, the at least one Dhq monomer has a structure of:. As may be appreciated, when formed in a synthetic compound, the Dhq monomer(s) can include derivatives of the above structure (e.g., Fmoc and / or -OH removed to form linkages with other monomers).

[0054] The at least one Dhq monomer can include any of the variations as described above. For example, the at least one Dhq monomer can include any of:S1647.188.111 (SRI-230078-PCT)

[0055] In some embodiments, the synthetic compound can include multiple Dhq monomers selected from the group consisting of: ,forms thereof. For example, a synthetic compound can include at least two, at least three, at least four, or all five of the above-listed Dhq monomers.

[0056] In some embodiments, the synthetic compound can include a plurality of amino acid monomers coupled to respective ones of a plurality of Dhq monomers and cleavage groups between at least portions of the plurality of Dhq monomers and the plurality of amino acid monomers. The cleavable groups can include phenyl-acetamido-methylene (PAM) groups. For example, the synthetic compound can include a Techneins® compound, as described above. In some such embodiments, the synthetic compound can include a plurality of molecules (e.g., ptych), each molecule including at least one Dhq monomer and at least one amino acid monomer and the cleavable groups between each of the plurality of molecules. The Dhq monomers, amino acid monomers, cleavable groups, and / or the molecules can be coupled together using fluorenylmethoxycarbonyl protecting group (Fmoc) solid phase peptide synthesis, as further described herein.

[0057] In some embodiments, the plurality of amino acid monomers can include non- natural amino acids, d-α-amino acids, and / or l-α-amino acids. In some embodiments, the amino acids are selected from Ala(Cp), Phe(4F), Ser(OMe), Ala, Gly, Phe, Val, d(Ala), d(Gly), d(Glu), and D(Lys), however embodiments are not so limited and can include other amino acids. As may be appreciated, Ala(Cp) includes and / or refers to an alanine amino acid modified with a cyclopropyl group (Cp), where the Cp is attached to the central carbon of the alanine side chain. Phe(4F) includes and / or refers to a phenylalanine amino acid modified with a fluorine group, where a hydrogen atom at the 4thposition on the aromatic ring of Phe is replaced by a fluorine atom (4F). Ser(OMe)S1647.188.111 (SRI-230078-PCT) includes and / or refers to a serine amino acid with a methyl ester group (-OCH3 or OMe) attached to the hydroxyl group on the side chain, replacing a hydrogen atom.

[0058] Various embodiments are directed to specific synthetic compounds, which can be selected from a plurality of synthetic compounds, each having at least one Dhq monomer, by screening the synthetic compounds for a function, such as to select affinity reagents that bind to particular targets.

[0059] In some embodiments, the synthetic compound includes: d(Glu)-DhqO-Phe(4F)-phenyl-acetamido-methylene (PAM)-d(Ala)-DhqY- Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE- Ala-PAM-DhqF-d(Lys)-Val-PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- PEG12-Gln(PEG-Biotin)-CONH2(e.g., 17077-35-1); Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM-PEG12-Gln(PEG-Biotin)-CONH2; (e.g., 17077-35-2); Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2 (e.g., 17077-35-3); PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2 (e.g., 17077-35-4); Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin)-CONH2(e.g., 17077-35- 5); d(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM (e.g., 17077-35-6); Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM (e.g., 17077-35-7);S1647.188.111 (SRI-230078-PCT) PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala)-PEG12-Gln(PEG-Biotin) (e.g., 17077-35-9); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin) (e.g., 76- 3); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-(L)Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Cys(alph-Gal)-CONH2(e.g., 17077-35-12); PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12-Cys(alpha-Gal)-CONH2 (e.g., 17077-35-13); PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12 (e.g., 17077-35-14); Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM- PEG12-Gln(PEG-Biotin) (e.g., 17077-52-18); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)-Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-1); d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-2); DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-3);S1647.188.111 (SRI-230078-PCT) d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)- Phe(4F)-PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-4); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-5); d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-6); d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM (e.g., 17107-91-7); DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM (e.g., 17107-91-8); DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-9); d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM-d(Lys)- DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY-d(Glu)- Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-10); DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(-Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-11); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-12); d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-13); DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-14);S1647.188.111 (SRI-230078-PCT) d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-15); d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM (e.g., 17107-91-16); d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-17); d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-18); d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val- PAM-DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqE-Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-19); d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-20); d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala-DhqE-Ala(Cp)-PAM (e.g., 17107-91-21); DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17107-91-22); DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17107-91-23); d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM- Ala-DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)- DhqY-Ala(Cp)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1- 1);S1647.188.111 (SRI-230078-PCT) d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)- DhqO-Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108- 1-2); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108-1-3); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)- CONH2(e.g., 17108-1-4); d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108- 1-5); DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-6); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-7); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-8); and d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-9).

[0060] In some embodiments, the synthetic compound is configured to bind to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to fentanyl, as further described herein.

[0061] In some embodiments Ala(Cp), Phe(4F), and Ser(OMe) can include:S1647.188.111 (SRI-230078-PCT) NH,

[0062] Some embodiments are directed to a synthetic compound comprising at least one Dhq monomer, wherein the synthetic compound is selected from: d(Glu)-DhqO-Phe(4F)-PAM-d(Ala)-DhqY-Ser(OMe)-PAM-d(Ala)-DhqE- Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE-Ala-PAM-DhqF-d(Lys)-Val- PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-PEG12-Gln(PEG-Biotin)- CONH2(e.g., 17077-35-1); Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM-PEG12-Gln(PEG-Biotin)-CONH2; (e.g., 17077-35-2); Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2(e.g., 17077-35-3); PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2 (e.g., 17077-35-4); Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin)-CONH2 (e.g., 17077-35- 5); d(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM (e.g., 17077-35-6);S1647.188.111 (SRI-230078-PCT) Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM (e.g., 17077-35-7); PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala)-PEG12-Gln(PEG-Biotin) (e.g., 17077-35-9); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin) (e.g., 76- 3); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-(L)Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Cys(alph-Gal)-CONH2(e.g., 17077-35-12); PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12-Cys(alpha-Gal)-CONH2 (e.g., 17077-35-13); PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12 (e.g., 17077-35-14); and Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM- PEG12-Gln(PEG-Biotin) (e.g., 17077-52-18).

[0063] In some such embodiments, the synthetic compound can bind to the spike protein of SARS-CoV-2, such as selectively binding to the spike protein of SARS-CoV- 2. As further described below, the synthetic compound or composition including the synthetic compound can further include other component(s) and / or can be used to diagnose and / or treat infection of SARS-CoV-2 in a subject, among other purposes.

[0064] As previously described, DhqB, DhqE, DhqF, DhqO, and DhqY can include:S1647.188.111 (SRI-230078-PCT)described, when formed in a synthetic compound, the Dhq monomer(s) can include derivative forms of the above structure (e.g., Fmoc and / or -OH removed to form linkages with other monomers).

[0065] Further, Ala(Cp), Phe(4F), and Ser(OMe) can include: NH, be appreciated, when formed in a synthetic compound, the modified amino acids can include derivatives (e.g., residues) of the above structure (e.g., Fmoc and / or -OH removed to form linkages with other monomers).

[0066] Some embodiments are directed to a synthetic compound comprising a plurality of Dhq monomers, a plurality of amino acid monomers, and cleavable groups between at least portions of the plurality of Dhq monomers and plurality of amino acid monomers. As further described herein, the synthetic compound can bind to fentanyl.

[0067] In some embodiments, the synthetic compound (e.g., a Techneins® compound) includes a plurality of molecules (e.g., ptych), each of the plurality of molecules including a subset of the plurality of Dhq monomers and the plurality of amino acidS1647.188.111 (SRI-230078-PCT) monomers and the cleavable groups between each of the plurality of molecules. For example and in some embodiments, the synthetic compound can include eight molecules, each of the eight molecules including three monomers including one Dhq monomers of the plurality of Dhq monomers and two of the plurality of the amino acid monomers, and one of the cleavable groups coupled to one of the three monomers.

[0068] As previously described, the plurality of Dhq monomers can have the structure of:wherein X is selected from C and N, and each R1and R2are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof.

[0069] In some embodiments, each of the plurality of Dhq monomers can have the structure of:, or a derivative thereof.

[0070] In some embodiments, each R1 and R2 are independently selected from H, phenol, O-allyl, and (CH2)2-COO-allyl.

[0071] In some embodiments, R1includes:

[0072] In some embodiments, R2 includes:.

[0073] In some embodiments, the plurality of Dhq monomers each include a structure selected from:S1647.188.111 (SRI-230078-PCT), as as

[0074] In some embodiments, the plurality of Dhq monomers are each selected from:S1647.188.111 (SRI-230078-PCT)derivatives thereof.

[0075] The plurality of amino acid monomers can be selected from: l-α-amino acids, d- α-amino acids, and non-natural amino acids of Ala(Cp), Phe(4F), Ser(OMe). In some embodiments, the l-α-amino acids, d-α-amino acids, and non-natural amino acids can include Ala(Cp), Phe(4F), Ser(OMe), Ala, Gly, Phe, Val, d(Ala), d(Gly), d(Glu), and d(Lys).

[0076] In some embodiments, the synthetic compound is selected from: d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)-Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-1); d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-2); DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-3); d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)- Phe(4F)-PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-4); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-5); d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-6); d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM (e.g., 17107-91-7);S1647.188.111 (SRI-230078-PCT) DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM (e.g., 17107-91-8); DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-9); d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM-d(Lys)- DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY-d(Glu)- Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-10); DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(-Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-11); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-12); d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-13); DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-14); d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-15); d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM (e.g., 17107-91-16); d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-17); d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-18);S1647.188.111 (SRI-230078-PCT) d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val- PAM-DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqE-Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-19); d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-20); d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala-DhqE-Ala(Cp)-PAM (e.g., 17107-91-21); DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17107-91-22); DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17107-91-23); d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM- Ala-DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)- DhqY-Ala(Cp)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108-1- 1); d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)- DhqO-Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108- 1-2); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-3); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)- CONH2 (e.g., 17108-1-4); d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-S1647.188.111 (SRI-230078-PCT) d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108- 1-5); DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-6); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-7); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-8); and d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-9).

[0077] As previously described, DhqB, DhqE, DhqF, DhqO, and DhqY can include:, as as

[0078] As further previously described, Ala(Cp), Phe(4F), and Ser(OMe) can include:S1647.188.111 (SRI-230078-PCT) NH Fmoc-NH O C OH(Fmoc-Ala(Cp)), (Fmoc-Phe(4F)), and Fmoc-NH O C MeO OH (Fmoc-Ser(OMe)), as well as derivatives thereof.

[0079] In some embodiments, the synthetic compound can bind to fentanyl, such as selectively binding to fentanyl. As further described below, the synthetic compound or a composition including the synthetic compound can further include other component(s) and / or can be used to treat fentanyl addiction and / or overdose, and / or to test for the presence of fentanyl in a subject (e.g., drug test), among other purposes.

[0080] Various embodiments are directed to methods of using any of the above- disclosed Dhq monomers and / or synthetic compounds. In some embodiments, the synthetic compound can be used to detect for the presence of a target, such as the spike protein of SARS-CoV-2 or fentanyl. In some such embodiments, the synthetic compound, or a composition including the synthetic compound, can include other component(s), such as a detection agent (e.g., fluorescent protein, dye, radioisotopes, enzymes). In some embodiments, in addition or alternatively to a detection agent, a complex including the synthetic compound bound to the target can be detected via an immunoassay or other types of assays in which the complex is captured via a capture agent and then detected. In some embodiments, detecting for the presence of the target can be used to diagnose a subject as being infected by SARS-CoV-2 and / or for drug testing a subject for use of fentanyl. For example, the method can include taking a sample from the subject, exposing the sample to the synthetic compound (or a composition including the synthetic compound), and detecting binding between the synthetic compound and a target.

[0081] In some embodiments, the synthetic compound can be used to treat a subject. For example, the synthetic compound or a composition including the synthetic compound can include other component(s) which are bound to the synthetic compound comprising at least one Dhq monomer and which have a therapeutic effect against SARS-CoV-2, prevent or mitigate the effects of fentanyl or overdoses of fentanyl, or otherwise impact fentanyl use. Some example components include active agents such as antivirals (e.g., nirmatrelvir-ritonavir, remdesivir, molnupiravir), ivermectin, hydroxychloroquine, zinc,S1647.188.111 (SRI-230078-PCT) monoclonal antibodies, naloxone, methadone, or buprenorphine, among other components and combinations thereof. In some embodiments, the method can include treating a viral infection or treating addiction or an overdose in a subject. For example, an effective amount of a synthetic compound or a composition including the synthetic compound can be administered to the subject, and in response, a viral infection, addiction, or overdose is treated. In some embodiments, the synthetic compound or composition including the synthetic compound can neutralize the target (e.g., kill). In some embodiments, the synthetic compound or composition including the synthetic compound can include other effects, such as but not limited to, weakening virions, activating or increasing the immune system response, lowering viral load, blocking receptors, blocking the effects of opiates on the brain, restoring breathing, metabolizing the target, and relieving withdrawal symptoms and / or cravings, among other effects and combinations thereof.

[0082] In such embodiments, delivery (or administration) of any synthetic compound and / or composition disclosed herein can be via a variety of mechanisms. In some embodiments, the compositions described herein can comprise a pharmaceutically acceptable carrier. By “pharmaceutically acceptable” is meant a material or carrier selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. Example carriers include dimyristoylphosphatidyl choline (DMPC), phosphate buffered saline or a multivesicular liposome. Other suitable pharmaceutically acceptable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A.R. Gennaro, Mack Publishing Company, Easton, PA 1995. Typically, an appropriate amount of pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic. Other examples of the pharmaceutically acceptable carrier include, but are not limited to, saline, Ringer’s solution and dextrose solution. The pH of the solution can be from about 5 to about 8, or from about 7 to about 7.5. Further carriers include sustained release preparations such as semi- permeable matrices of solid hydrophobic polymers containing the composition, which matrices are in the form of shaped articles, e.g., films, stents (which are implanted in vessels during an angioplasty procedure), liposomes or microparticles. It will be apparent to those skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. These can include standard carriers for administrationS1647.188.111 (SRI-230078-PCT) of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.

[0083] Pharmaceutical compositions can also include carriers, thickeners, diluents, buffers, preservatives and the like, as long as the intended activity of the composition is not compromised. Pharmaceutical compositions can also include one or more active agents (in addition to the composition described herein) such as antiviral agents, anti- inflammatory agents, and anesthetics, among others such as those described above. The pharmaceutical composition can be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated.

[0084] Preparations of parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

[0085] Formulations for optical administration can include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like can be used.

[0086] Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders may be desirable. Some compositions can be potentially be administered as a pharmaceutically acceptable acid- or base- addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mon-, di-, trialkyl and aryl amines and substituted ethanolamines.S1647.188.111 (SRI-230078-PCT)

[0087] Embodiments are not limited to those listed above, and can include various different examples, at least some of which are listed below.

[0088] Example A1. A dihydroisoquinolinone (Dhq) monomer comprising:wherein: X is selected from C and N; and each R1and R2are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof.

[0089] Example A2. The Dhq monomer of Example A1, wherein the monomer comprises the structure of:.

[0090] Example A3 The Dhq monomer of Example A1, wherein each R1and R2are independently selected from H, phenol, O-allyl, and (CH2)2-COO-allyl.

[0091] Example A4. The Dhq monomer of Example A1, wherein R1 comprises:

[0092] Example A5. The Dhq monomer of Example A1, wherein R2comprises:

[0093] Example A6. The Dhq monomer of Example A1, wherein the Dhq monomer is selected from:S1647.188.111 (SRI-230078-PCT)

[0094] Example A7. The Dhq monomer of Example A1, wherein the Dhq monomer isS1647.188.111 (SRI-230078-PCT)

[0095] Example B1. A synthetic compound at least one dihydroisoquinolinone (Dhq) monomer having a structure of:wherein: X is selected from C and N; and each R1 and R2 are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof.

[0096] Example B2. The synthetic compound of Example B1, wherein the at least one Dhq monomer includes the structure of:.

[0097] Example B3. The synthetic compound of Example B1, wherein each of the at least one DHQ monomer is selected from:S1647.188.111 (SRI-230078-PCT)

[0098] Example B4. The synthetic compound of Example B1, including at least three Dhq monomers selected from the group consisting of:

[0099] Example B5. The synthetic compound of Example B1, wherein each of the at least one Dhq monomer is selected from:S1647.188.111 (SRI-230078-PCT)

[0100] Example B6. The synthetic compound of Example B1, further including at least one amino acid monomer coupled to respective ones the at least one Dhq monomer and phenyl-acetamide-methylene (PAM) groups between at least portions of the at least one Dhq monomer and the at least one amino acid monomer.

[0101] Example B7. The synthetic compound of Example B6, wherein the at least one Dhq monomer includes a plurality of Dhq monomer and the at least one amino acid monomer includes a plurality of amino acid monomers which are coupled together using Fmoc solid phase peptide synthesis.

[0102] Example B8. The synthetic compound of Example B6, wherein the at least one amino acid includes a plurality of amino acids that are non-natural amino acids, d-α- amino acids, l-α-amino acids, and combinations thereof.

[0103] Example C1. A synthetic compound comprising at least one dihydroisoquinolinone (Dhq) monomer, wherein the compound is selected from: d(Glu)-DhqO-Phe(4F)-phenyl-acetamido-methylene (PAM)-d(Ala)-DhqY- Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE- Ala-PAM-DhqF-d(Lys)-Val-PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM; Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM; Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala); PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala);S1647.188.111 (SRI-230078-PCT) Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM; d(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM; Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM; PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-(L)Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe); and Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM.

[0104] Example C2. The synthetic compound of Example C1, further including PEG and / or Biotin on the C-terminus of the synthetic compound.

[0105] Example C3. The synthetic compound of Example C1, further including Gln(PEG-Biotin)-CONH2 on the C-terminus of the synthetic compound.

[0106] Example C4. The synthetic compound of Example C1, further including PEG12- Gln(PEG-Biotin) or PEG12-Gln(PEG-Biotin)-CONH2on the C-terminus of the synthetic compound.

[0107] Example C5. The synthetic compound of Example C1, further including PEG12 CONH2or PEG12on the C-terminus of the synthetic compound.

[0108] Example C6. The synthetic compound of Example C1, further including PEG12-Cys(alpha-Gal)-CONH2 on the C-terminus of the synthetic compound.S1647.188.111 (SRI-230078-PCT)

[0109] Example C7. The synthetic compound of Example C1, wherein the synthetic compound binds or selectively binds to the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0110] Example D1. A synthetic compound comprising at least one dihydroisoquinolinone (Dhq) monomer, wherein the compound is selected from: d(Glu)-DhqB-Ala-phenyl-acetamido-methylene (PAM)-d(Glu)-DhqB- Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)-PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)- Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly- PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)- Phe(4F)-PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM; DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM;S1647.188.111 (SRI-230078-PCT) d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM-d(Lys)- DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY-d(Glu)- Phe-PAM-DhqE-Gly-Phe(4F)-PAM; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(-Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val- PAM-DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqE-Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM;S1647.188.111 (SRI-230078-PCT) d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala-DhqE-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM; d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM- Ala-DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)- DhqY-Ala(Cp)-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)- DhqO-Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM; andS1647.188.111 (SRI-230078-PCT) d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM.

[0111] Example D2. The synthetic compound of Example D1, further including PEG and / or Biotin on the C-terminus of the synthetic compound.

[0112] Example D3. The synthetic compound of Example D1, further including PEG12-Gln(Biotin)-CONH2on the C-terminus of the synthetic compound.

[0113] Example D4. The synthetic compound of Example D1, further including Gln(PEG-Biotin)-CONH2 on the C-terminus of the synthetic compound.

[0114] Example D5. The synthetic compound of Example D1, further including PEG12-Gln(PEG-Biotin) or PEG12-Gln(PEG-Biotin)-CONH2on the C-terminus of the synthetic compound.

[0115] Example D6. The synthetic compound of Example D1, further including PEG12CONH2on the C-terminus of the synthetic compound.

[0116] Example D7. The synthetic compound of Example D1, further including PEG12-Cys(alpha-Gal)-CONH2 on the C-terminus of the synthetic compound.

[0117] Example D8. The synthetic compound of Example D1, wherein the synthetic compound binds or selectively binds to fentanyl.

[0118] Disclosed are materials, synthetic compounds, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed method and compounds. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a compound is disclosed and discussed and a number of modifications that can be made to a number of monomers and compound are discussed, each and every combination and permutation of the compounds and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, is this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from disclosure of A, B,S1647.188.111 (SRI-230078-PCT) and C; D, E, and F; and the example combination A-D. Likewise, any subset or combination of these is also specifically contemplated and disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed compounds. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.

[0119] It is understood that the disclosed synthetic compounds, compositions, and methods are not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0120] As used herein and in the appended claims, the singular forms "a ", "an", and "the", as well as “at least one” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "at least one Dhq monomer" or includes a plurality of such Dhq monomers, such as two, three, four, or more, and equivalents thereof known to those skilled in the art, and so forth.

[0121] As used herein, “synthetic” includes and / or refers to compounds that are not naturally occurring. Example synthetic compounds can be formed of amino acid monomers and non-amino acid monomers (e.g., Dhqs) covalently linked together.

[0122] Techneins® compounds and / or libraries include and / or refer to synthetic polymers made up of covalently linked monomers that are amino acids and monomers that are not amino acids and / or a plurality thereof (e.g., a library). The amino acids may be, for example, d-α-amino acids (e.g., d(Glu(tBu)); d(Lys)), l-α-amino acids, beta- amino acids, gamma-amino acids, or combinations thereof. Non-limiting examples of monomers that can be used for Techneins® compounds may be found in the figures and include cleavable groups (e.g., PAM), DhqF, DhqB, DhqO, DhqY, DhqE, N-substituted glycines, triazines, pyrimidines, and combinations thereof. A cleavable group includes and / or refers to a functional group that cleaves to chemically separate molecules from one another and / or the compound from a bead. As may be appreciated, two amino acids can covalently link together via the amino group of one amino acid joining with theS1647.188.111 (SRI-230078-PCT) carboxyl group of another amino acid. Similarly, a Dhq monomer can covalently link with another monomer, such as an amino acid, via the amino group of one monomer joining with the carboxyl group of another monomer. In some instances, a L-α-amino acid monomer can include PAM, and the L-α-amino acid monomer with PAM can link with another monomer, such as a Dhq or another monomer, via the amino group of the other monomer joining with the carboxyl group of PAM.

[0123] Amino acids include and / or refer to molecules that contain amino and carboxylic acid functional groups. The amino acid abbreviations used herein include the convention three letter codes for the amino acids and are expressed as follows: Ala (A), alanine; Cys (C), cysteine; Asp (D), aspartic acid; Glu (E), glutamic acid; Phe (F), phenylalanine; Gly (G), glycine; His (H), histidine; Ile (I), isoleucine; Lys (K), lysine; Leu (L), leucine; Met (M), methionine; Asn (N), asparagine; Pro (P), proline; Gln (Q), glutamine; Arg (R), arginine; Ser (S), serine; Thr (T), threonine; Val (V), valine; Tyr (W), tryptophan; and Tyr (Y), tyrosine. The amino acids can include l- and d-amino acids, with the d-α-amino acids being identified herein as “d(XXX)”, such as d(Glu) and the l-α-amino acids being identified without any further clarification (e.g., Glu). Amino acids can include modified forms, such as those described above.

[0124] Polypeptide, as used herein, includes and / or refers to any peptide, oligopeptide, polypeptide, gene product, expression product, or protein. A polypeptide is comprised of consecutive amino acids. The term "polypeptide" encompasses naturally occurring or synthetic molecules.

[0125] In addition, as used herein, peptide includes and / or refers to includes amino acids joined to each other by peptide bonds or modified peptide bonds, e.g., peptide isosteres, etc. and may contain modified amino acids other than the 20 standard protein building block amino acids. The peptides can be modified by either natural processes, such as post-translational processing, or by chemical modification techniques which are well known in the art. Modifications can occur anywhere in the polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. The same type of modification can be present in the same or varying degrees at several sites in a given peptide. Also, a given polypeptide can have many types of modifications. Modifications include, without limitation, acetylation, acylation, ADP- ribosylation, amidation, covalent cross-linking or cyclization, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalentS1647.188.111 (SRI-230078-PCT) attachment of a phosphytidylinositol, disulfide bond formation, demethylation, formation of cysteine or pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristolyation, oxidation, PEGylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, and transfer-RNA mediated addition of amino acids to protein such as arginylation. (See Proteins —Structure and Molecular Properties 2nd Ed., T.E. Creighton, W.H. Freeman and Company, New York (1993); Posttranslational Covalent Modification of Proteins, B.C. Johnson, Ed., Academic Press, New York, pp.1-12 (1983)). N-terminus of a peptide (or amino acid or other molecule) refers to or includes an end with a free amino group. The C-terminus of a peptide (or amino acid or other molecule) refers to or includes an end with a free carboxyl group.

[0126] As used herein, effective amount of a synthetic compound or composition includes and / or refers to a sufficient amount of the synthetic compound or composition to provide the desired effect. The exact amount can vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of disease or condition that is being treated, the particular synthetic compound or composition used, its mode of administration, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate “effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.

[0127] As used herein, affinity reagent includes and / or refers to a synthetic compound that binds to specific substance (e.g., the targe), such as proteins or nucleic acids. Further, “selectively binds”, “specifically binds”, and “preferentially binds” includes and / or refers to a compound recognizes and physically interacts with its target and does not significantly recognize and interact with other targets.

[0128] As used herein, “treat” includes and / or refers to administering a synthetic compound or composition of the invention to a subject, such as a human or other mammal (for example, an animal model), that has a disease or condition, in order to prevent or delay a worsening of the effects of the disease or condition, or to partially or fully reverse the effects of the disease or condition. In some embodiments, the disease or condition is a SARS-CoV-2 viral infection. In some embodiments, the disease or condition is fentanyl addiction or overdose. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition and / or to a subject who exhibits only early signs of a disease, disorder, and / or condition for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / orS1647.188.111 (SRI-230078-PCT) condition. In some embodiments, treatment comprises delivery of at least one of the disclosed compound or compositions to a subject.

[0129] As used herein, “prevent” includes and / or refers minimizing the chance that a subject who has an increased susceptibility for developing disease, disorder or condition will develop the disease, disorder, condition, or death therefrom.

[0130] As used herein, subject includes and / or refers the target of administration, diagnosis, and / or a test, e.g., a human. Thus, the subject can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. The term subject can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). In some embodiments, a subject is a mammal. In some embodiments, a subject is a human. The term does not denote a particular age or sex. Thus, adult, child, adolescent, and newborn subjects and fetuses, whether male or female, are intended to be covered.

[0131] A patient includes and / or refers to a subject afflicted with a disease, a disorder, or a condition. For example, the term "patient" includes human and veterinary subjects. In some embodiments, the “patient” has been diagnosed with a need for treatment prior to the administering step.

[0132] Substitutions, deletions, insertions, or any combination thereof may be used to arrive at a final derivative, variant, or analog. Generally, these changes are done on a few nucleotides to minimize the alteration of the molecule. However, larger changes may be tolerated in certain circumstances.

[0133] Throughout the description and claims of this specification, the words “include” and / or “comprise” and variations of the word, such as “including”, “includes, “comprising”, and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. In particular, in methods comprising one or more steps or operations it is specifically contemplated that each step comprises what is listed (unless that step includes a limiting term such as “consisting of”), meaning that each step is not intended to exclude, for example, other additives, components, integers or steps that are not listed in the step.

[0134] The skilled artisan would recognize that various terminology as used in the Specification (including claims) connote a plain meaning in the art unless otherwise indicated. For example, unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed methods, compounds, and / or methods belong. Although anyS1647.188.111 (SRI-230078-PCT) methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present methods, compounds, and / or compositions, the particularly useful methods, devices, and materials are as described. Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. No admission is made that any reference constitutes prior art. The discussion of references states what their authors assert, and applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of publications are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.

[0135] Various embodiments are implemented in accordance with the underlying Provisional Application No.63 / 539,286, filed September 19, 2023, and entitled “Novel Dihydroisoquinoline-Based Monomer Building Blocks for Non-Natural Polymers”, to which benefit is claimed and which is fully incorporated herein by reference in its entirety for its general and specific teachings. For instance, embodiments herein and / or in the Provisional Application can be combined in varying degrees (including wholly). Reference can also be made to the experimental teachings and underlying references provided in the underlying Provisional Application. Embodiments discussed in the Provisional Application are not intended, in any way, to be limiting to the overall technical disclosure, or to any part of the claimed disclosure unless specifically noted. EXPERIMENTAL EMBODIMENTS

[0136] Various experimental embodiments were directed to forming Dhq monomers and synthetic compounds comprising at least one Dhq monomer. Some experimental embodiments were directed to screening a library for synthetic compounds having affinity for specific targets, including but not limited to the spike protein of SARS-CoV- 2 and fentanyl. Further experiments were directed to further assessing the properties of such synthetic affinity reagents.

[0137] Structural biology operates on the fundamental premise that the function of a protein is intricately tied to its three-dimensional structure, which, in turn, is dictated by its primary sequence. Consequently, the predominant focus of molecular biotechnology has revolved around understanding folded globular proteins. This emphasis on structure and function extends to the exploration of sequence-defined polymers (SDPs),S1647.188.111 (SRI-230078-PCT) composed of non-natural building blocks, which aims to replicate protein-like secondary and tertiary structures. Within this realm, SDPs are called foldamers which can be defined as any oligomer that folds into a conformationally ordered state in solution, the structures of which are stabilized by a collection of noncovalent interactions between nonadjacent monomer units. The allure of SDPs lies in the potential to unlock new classes of molecular interactions and assemblies, offering enhanced physical, chemical, and biological properties customizable through synthetic modification, and leveraging the biotechnology revolution that has been driven by the engineering of natural biopolymers. SDPs can expand the discovery of novel reagents, therapeutics, materials and catalysts in pharmaceuticals, agrochemicals, diagnostics, and materials science.

[0138] Beyond the realm of structured proteins lies the proteome's lesser-explored territory, encompassing intrinsically disordered proteins (IDPs) which exist as dynamic equilibria of unfolded sequences6 and partially folded secondary structural conformations that form molten globule-like structures. Despite the dogma that structure defines function, disordered proteins have a significant role in biomolecular recognition, such as modulating protein–protein and protein–DNA interactions, mediating biomolecular assembly and controlling signaling pathways. To explain this, prior solutions proposed a structure-function continuum with complementarity between structured and disordered proteins whereby, broadly speaking, catalysis and transport functions are controlled by ordered proteins, while regulation, recognition and signaling are controlled by intrinsically disordered proteins and protein regions. Unlike structured proteins that exhibit defined binding interactions, IDPs exhibit a wide range of binding modes from disordered dynamic multivalent interactions (so called “fuzzy” binding) to induced folding to form stable tertiary structures with their binding partners. As a result, they often exhibit multifunctionality and binding promiscuity which is evolutionarily desirable in signaling pathways where relative affinities and concentrations of binding partners control switching mechanisms. While X-ray crystallography and cryo-electron microscopy (cryo-EM) have streamlined structure determination for folded proteins, unraveling the conformational ensembles and binding properties of IDPs remains a formidable challenge and they have therefore received relatively little focus despite the fact that IDPs make up 34 percent (%) of the human proteome and >52% of human proteins have intrinsically disordered regions of >30 residues.

[0139] To date, synthetic biologic or non-natural SDPs of IDPs remain undocumented, leaving a gap in understanding their behavior and potential applications. Using aS1647.188.111 (SRI-230078-PCT) screening approach and unique polymer library design, a class of designer synthetic polymers called “Techneins® compounds” have been developed, and their utility as synthetic IDPs with drug-like properties has been assessed in screening against the SARS-CoV-2 spike protein, fentanyl, and other targets. Structure-activity relationship (SAR) studies of the lead Techneins® compound, compound 1, demonstrate a multivalent dynamic binding mechanism which has previously not been explored through chemically synthetic molecules. Intriguingly, this binding mode is sequence independent with regard to the Techneins® compound but is broadly specific for SARS- CoV-2 variants compared to other coronaviruses and glycoproteins.

[0140] Techneins® Concept and Design

[0141] Various embodiments were directed to the design of synthetic compounds, e.g., the Techneins® compounds. Techneins® compounds are sequence-defined synthetic polymers made up of Dhq and other non-Dhq (e.g., amino acids and cleavable group) building blocks which are used to explore novel structure space and molecular recognition modes.

[0142] As previously described, criteria for selecting non-natural monomer building blocks include chemical accessibility and functional diversity, chiral rigidity to favor local secondary structure and yet conformational flexibility to allow potential folding and inducible binding. Tolerance to orthogonal chemistry steps in building the polymer by solid phase peptide synthesis (SPPS) methods and chemical fragmentation for sequencing are also beneficial. Dhq monomers are efficiently synthesized as a mixture of trans enantiomers via a two step synthesis in >90% yields based on a modification of the Castagnoli-Cushman reaction, which are separated by supercritical fluid chromatography (SFC) to produce each monomer in >50 gram (g) scale (see FIG.1A). The Castagnoli-Cushman reaction is described in Cushman et. al, “The condensation of succinic anhydrides with Shiff bases. Scope and mechanism”, J Org Chem, 36, 3404- 3411 (1971), which is incorporated herein in its entirety for its teachings. The Dhq monomers incorporated backbone carboxylic acid and Fmoc-protected amine (see FIG. 1B). The side chains of the five Dhq monomers were introduced through a selection of aromatic aldehyde building blocks with allyl protecting groups where appropriate. These side chains encompass a variety of properties including acidity, hydrophobicity and hydrophilicity, as well as hydrogen bond donors and acceptors. Overall, Dhq monomersS1647.188.111 (SRI-230078-PCT) had similar physicochemical properties to natural building blocks but displayed more organic characteristics such as increased lipophilicity.

[0143] FIGs.1A-1C illustrate example synthesis and characterization of Dhq monomers. FIG.1A shows an example synthesis scheme and enantiomer separation of Fmoc N-protected Dhqs by SFC. FIG.1B shows Dhq monomers used in various embodiments. Fast eluting enantiomers are shown on the left (-) and uniformly show negative specific rotation. Slow eluting enantiomers shown om the right (+) have positive specific rotation. FIG.1C shows example crystal structure of Fmoc (-) S,S DhqB-OH, which shows an internal hydrogen bond between the backbone NH and ring lactone carbonyl demonstrating a turn-like structure.

[0144] In various embodiments, the specific rotation of each pair of the five Dhq diastereomers showed that the earlier eluting peak in the chiral separation has a negative specific rotation ( / or (-)), and the later eluting peak had a positive specific rotation (d or (+)) (FIG.1B). Powder x-ray crystallography of Fmoc-(-)-DhqB-OH (FIG.1C) determined this to be the S,S enantiomer which is inferred to be the same for the other (-)-Dhq monomers, and therefore the (+)-Dhqs are the R,R configuration. The Fmoc-(-)- DhqB-OH crystal structure revealed a trans axial boat conformation with the aromatic sidechain and carboxylic acid groups projecting above and below the lactam ring of the Dhq core. Hydrogen bonding between the backbone NH and the quinoline carbonyl is observed in the crystal structure. The Dhq monomers in the synthetic compounds are in the S,S enantiomer configurations, unless noted otherwise. For example, Dhq monomers in an R,R enantiomer configuration are denoted by a (+) in front of the Dhq monomer.

[0145] Techneins® library production and screening against SARS-CoV-2 spike receptor binding domain (SRBD)

[0146] Various embodiments were directed to the production of a Techneins® library and screening against targets. The Techneins® library was generally designed as described in Avital-Shmilovici, et al., “Mega-High-Throughput Screening Platform for Discovery of Biologically Relevant Sequence-Defined Non-Natural Polymer”, ACS Cent Sci, 8, 86-101 (2022), which is incorporated herein in its entirety for its teachings, and whereby each synthetic compound (e.g., polymer) was composed of a number of ptych units as the diversity elements making up the sequence. Each ptych was made up of a selection of diverse building block monomers and a backbone cleavable monomer. Ptychs can have any number of monomers (e.g., three = triptych, four = tetraptych, fiveS1647.188.111 (SRI-230078-PCT) = pentaptych). Library designs can have any number of ptychs depending on the application being tested. Each diversity position in the polymer is made up of a diverse set of ptychs, each with a unique molecular weight such that screening hits can be chemically cleaved into the base ptychs which can then be read as a unique barcode by high resolution liquid chromatography with tandem mass spectrometry (LCMS / MS) to identify the original polymer sequence.

[0147] FIGs.2A-2D illustrate the design of a Techneins® library. The Techneins® library used in experimental embodiments comprised 16.7 million members which incorporated the five (-)-Dhq monomers (Dhq(x)) combined with 11 non-natural and natural d- and l-α-amino acids (Y or Z) and the PAM ester base-cleavable linker to create a tetraptych design library of eight tandem repeats of Dhq(x)-Y-Z-PAM or Y- Dhq(x)-Z-PAM (see FIGs.2A-2B). This tandem repeat design is similar to tandem repeats seen in IDPs in nature and served as the basis for and the library design to discover IDP-like mimetics.

[0148] To model the system, the Techneins® library was screened against the SARS- CoV-2 SRBD from the 2019n-CoV / USA_WA1 / 2020 strain19 (hence forward called wild type or wt SRBD) using the Fiber-optic Array Scanning Technology (FAST) screening platform previously described in Avital-Shmilovici, et al., “Mega-High- Throughput Screening Platform for Discovery of Biologically Relevant Sequence- Defined Non-Natural Polymer”, ACS Cent Sci, 8, 86-101 (2022). The spike protein binds the human Angiotensin-Converting Enzyme 2 (ACE2) receptor as the first step in viral entry and has been a primary target of antibody and vaccines. However, the emergence of new variants necessitates ongoing efforts to develop effective treatments.

[0149] FIG.2A illustrates example Techneins® compounds in the library and FIG.2B illustrates building blocks used to form the Techneins® compounds. More specifically, FIG.2A shows the mix-and-split strategy used to make twenty copies of a 16.7 million member library synthesized on 492 milligrams (mg) of 10 micron diameter 0.22 millimole (mmol) / loading TentaGel® beads. Eight ptychs were incorporated to create polymers that were 32 monomers long with an average molecular weight of around 6 kilodalton (KDa). For each ptych position, there are eight possible tetraptychs as the diversity elements. Each tetraptych diversity element (8 x 8 = 64) has a unique signal detectable by LCMS / MS which enables identification for sequencing after backbone cleavage. A portion of the library was screened as described in Dauter, et. al, “Progress in protein crystallography”, Protein Pept Lett, 23, 201-210 (2016), against AF555S1647.188.111 (SRI-230078-PCT) labeled SRBD in 20 percent (%) human serum / Odyssey / CHAPS blocking buffer to minimize nonspecific binding, wherein is incorporated herein by reference in its entirety for its teachings. FIG.2B illustrates structures of Dhq set and other building blocks used in library production. FIG.2C illustrates the chemical structure of resynthesized compound 1. C-terminal biotinylated analogues were used for follow-up assays. FIG. 2D is a table and graph of BLI binding done in 20 millimolar (mM) 3-(N- morpholino)propanesulfonic acid (MOPS) / 25mM KCl / 0.02% Tween™20 at pH 7.4. Biotinylated Techneins® compounds (25 nanomolar (nM) loading concentration) were immobilized on streptavidin coated BLI biosensors and spike proteins were in solution.

[0150] Screening hits were resynthesized as full amide backbone Techneins® compounds, replacing the ester bonds on the X-PAM cleavage sites in the corresponding sequences in the library (see FIG.2C). For several of the assays as detailed below, lead hits were synthesized with a C-terminal biotin handle connected through a PEG12linker for immobilization or detection. Hit binding to SRBD was confirmed by microscale thermophoresis (MST) and Enzyme-Linked Immunosorbent Assay (ELISA). Binding kinetics were measured for several of the lead Techneins® compounds by bio-layer interferometry (BLI) to obtain quantitative konand koffrates and KD. Multiple nanomolar hits were identified from the primary screen. For various experiments, the Techneins® compound 1 (e.g., SRI-89-8) (see FIG.2C) was used, which has a binding KD of 16.1nM to SRBD and notably ten-fold higher affinity of 1.6nM to full spike protein which incorporates the S1 and S2 subunits (see FIG.2D). Compound 1 (SRI-89-8) includes: d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala- PAM-DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM.

[0151] Structure activity relationship (SAR) assessment of compound 1 indicates a multivalent binding mode that is not sequence dependent

[0152] In some experiments, a preliminary SAR analysis study was performed to identify the key parts of the sequence that were critical for binding and to characterize binding properties. A truncation study was conducted where tetraptychs were serially deleted from the N- and C-termini exhibited affinities to SRBD ranging from 25% to 50% of the activity of full-length compound 1, indicating that the whole sequence may be required for high-affinity binding, with a slight preference for binding observed for the N-terminal ptychs (see FIG.3A). Serial deletion of PAM residues throughout theS1647.188.111 (SRI-230078-PCT) sequence showed minor improvements on affinity in all cases compared to compound 1 (see FIG.3A). Full deletion of all PAM residues (compound 2) also showed a similar affinity to spike protein as full-length compound 1 as measured by ELISA (not shown) and BLI with a KDof 4.7nM (see FIG.3B). These results suggest that the PAM residues play little role in binding or conformational stability in intermolecular interaction and that binding is focused around the Xaa-Dhq-Xaa and Dhq-Xaa-Xaa regions. Interestingly, pan replacement of all Xaa N-terminal to Dhqs by Gly in compound 1 (compound 3) lost all activity in ELISA and pan replacement of Dhqs with PAM (compound 4) showed greatly reduced binding. However, similar pan substitution of Xaa C-terminal to Dhqs (compound 5) showed >2-fold improved activity (see FIG.3C). The replacement of all Xaa’s N- and C-terminal to Dhqs (compound 6) also lost binding activity consistent with N-Xaa’s being critical for binding across all ptychs.

[0153] FIGs.3A-3E illustrate the preliminary SAR data for compound 1. Percent values are ELISA comparison to C-terminal biotinylated compound 1 immobilized on streptavidin coated plates with labeled SRBD in solution. KDs are for biotinylated compound 1 immobilized on BLI surface with Spike protein in solution. FIG.3A shows data for systematic truncation of ptych regions from N- and C-termini of compound 1. FIG.3B shows data for a compound with serial and pan deletion of PAM residues from compound 1, which is referred to as compound 2. FIG.3C shows data for compounds with pan substitution of Xaa-DhqYaa residues from compound 1, which are referred to as compounds 3, 4, 5, and 6. FIGs.3D-3E show data for compounds with scrambled, randomized, inversed, and enantiomer sequences of compound 1 (SRI-89-8), which are referred to as compounds 7, 8, 9, 10, 11, 12, and 13.

[0154] The SAR results showed that the full-length sequence may be required for optimal binding and that Xaa-Dhq represents the core molecular recognition feature (MoRF) in each ptych. Overall, this indicated that compound 1 (e.g., SRI-89-8) exhibits multivalent binding where each ptych MoRF is required but no one MoRF is critically important in binding affinity over the others. This result is consistent with IDP-like multivalent binding, which is generally dynamic, meaning each MoRF binds to multiple contact sites on the target protein in a dynamic ensemble of binding conformations.

[0155] To assess whether the binding interaction of compound 1 is sequence- independent, various embodiments were directed to testing increasingly sequence scrambled analogs. Sequence scrambling was achieved using a random number generator to assign the new positions of residues in each scrambled design to remove theS1647.188.111 (SRI-230078-PCT) possibility of human bias. Starting conservatively, the positions of residues were randomized within each ptych (compound 7) and then scrambled the order of the ptychs themselves (compound 8) (see FIG.3D). Surprisingly, both analogs exhibited full binding comparable to compound 1, e.g., SRI-89-8. In some embodiments, three fully randomized sequences of compound 1 were generated. The first of the scrambled sequences (compound 9) showed around 90% binding of compound 1 and compounds 10 and 11 had equal or better activity as measured by ELISA. BLI showed that compound 11 has somewhat improved binding to the full spike protein with a sub nanomolar KD of 0.77nM over compound 1 (KD 1.6nM) which confirmed that sequence is not critical for binding but relative sequence organization can influence affinity.

[0156] The reverse sequence (compound 12) shows similar activity to compound 1. Given the synthetic accessibly of Techneins® compounds over natural biopolymers, embodiments included testing the enantiomer compound 13 of compound 1 where each residue chiral center in the sequence was inverted and this also showed similar activity as compound 1. This supports that binding interactions are largely mediated through sidechain contacts of the Techneins® compounds.

[0157] Sequence independent binding seemed to be at odds with the initial SAR study which showed that MoRFs in the lead series are focused around the Xaa-Dhqs pharmacophore. Truly sequence independent binding would suggest that the compound composition is more important than sequence as has indicated for some IDPs. However, when comparing the compound 1 with scrambled compound 11, compound 1 notably has two Gly-Dhq MoRFs which from the example of compound 3 are known to be deleterious for affinity. Compound 11, on the other hand, had only Xaa-Dhq, PAM-Dhq and Dhq-Dhq motifs, suggesting that a functional amino acid in the Xaa position of the “Xaa”-Dhq MoRF may be optimal for binding regardless of the composition. It is also evident that the relative ordering of the MoRFs is not critical but distance between them may be optimizable in further SAR development.

[0158] Techneins® compounds binding is specific and shows broad spectrum affinity for SARS-CoV-2 variants

[0159] The observation that sequence is not critical for affinity of the peptide-like synthetic polymers would typically raise concerns of nonspecific binding. To mitigate this possibility, a primary screen was conducted in the presence of a complex biological buffer, aiming to mask out nonspecific interactions between the fluorescently labeledS1647.188.111 (SRI-230078-PCT) target and the bead-bound Techneins® compounds. To confirm selective binding, ELISA binding of SRBD to immobilized compound 1 was conducted in the presence of 0.2% human serum which showed only a 30% reduction in binding compared to the 1% Bovine serum albumin (BSA) control (see FIG.4B). No significant further reduction was observed upon increasing human serum concentration to 5%.

[0160] FIGs.4A-4C illustrate data on the stability and selectivity of compound 1. Specifically, FIG.4A is a graph showing compound 1 stability in human serum compared to a control peptide. FIG.4B is a graph showing the effects of increasing concentration of human serum on binding affinities by ELISA. FIG.4C includes graphs showing the selectivity profile of compound 1and scrambled compound 11 to SARS- CoV spike protein variants compared to seasonal human coronavirus spike proteins, as well as other viral antigenic proteins and glycoproteins.

[0161] In such embodiments, compound 1 was screened against a selectivity panel comprising SARS-CoV-2 SRBD and spike protein variants, seasonal human coronavirus (HCoV) spike protein variants, and four unrelated glycoproteins (see FIG. 4C). Intriguingly, compound 1 exhibited cross-reactive selectivity to all tested SARS- CoV-2 variants, including key mutant N501Y and omicron SRBD and spike proteins S1 subunits, while showing no affinity to HCoV spike S1 variants or other unrelated glycoproteins. Notably, the increased affinity of compound 1 to omicron SRBD observed in ELISA was confirmed in BLI, with a KDof 3.8nM compared to wild type SRBD with a KD of 16.1nM. Various embodiments were directed to testing compound 1 in cell surface spike protein-expressing HEK293 cells compared to wild-type cells and observed selective binding to the spike-expressing cell line, as further described herein.

[0162] These results collectively demonstrated the specific binding of compound 1 and variants thereof to SARS-CoV-2 SRBD across a variety of native constructs and variants in biological buffers, with minimal or no binding to unrelated proteins. This indicates potent and selecting binding of Techneins® compounds. Significantly, the scrambled compound 11 demonstrated better broad-spectrum selectivity and binding potency for SARS-CoV-2 variants than compound 1, further suggesting that, while sequence is not critical for selectivity, it can be optimized.

[0163] Characterization of compound 1-SRBD binding interaction

[0164] Attempts to crystalize compound 1 by itself or in the presence of SRBD were unsuccessful which was consistent with the IDP-like character of this Techneins®S1647.188.111 (SRI-230078-PCT) compound. As an alternative approach, a pepscan of the SRBD protein to identify the binding epitopes of compound 1 was used to explore which regions are involved in binding. Fifteen overlapping peptide segments of 30 residues were synthesized on beads and screened for SRI-89-8 binding (see FIG.5A). Neutralizing antibody (Sino-Bio- 40591-MM43, a mouse monoclonal for SARS-CoV-2 spike protein 2019-nCoV) exhibited no significant binding to any of these fragments consistent with a requirement for a tertiary discontinuous structural epitope. By contrast, significant Techneins® compound binding to many of the fragments was evident with preference for the N- terminal region (Pep1) and contact regions of the hACE2 receptor binding motif (Pep9 and 12) (see FIG.5A) which corresponds to two of the three intrinsically disordered regions in the SRBD. See Quaglia, et al., “SARS-CoV-2 variants preferentially emerge at intrinsically disordered protein sites helping immune evasion”, Febs J, 289, 4240- 4250 (2020), which is incorporated herein by reference in its entirety for its teachings. Notably Pep1, 9, and 12 are co-located in the crystal structure of the SRBD “locked down” and to a lesser extent in the hACE2 receptor binding “extended” conformation of the spike protein (see FIG.5B). This suggests that the Techneins® compound hits bind SRBD in this tertiary folded state more favorably than the open hACE binding conformation. The colocation of the locked down SRBD subunits of the spike protein trimer may also account for the ten-fold improved binding of compound 1 over SRBD alone through an avidity effect.

[0165] FIGs.5A-5D illustrate data characterizing compound 1 binding interaction with SARS-CoV-2 SRBD. FIG.5A illustrates the SRBD domain on S1 subunit of the spike protein and a pepscan showing degree of binding of compound 1 to SRBD segments. FIG.5B includes illustrations of space filling models of the crystal structures of SRBD showing compound 1 binding region as indicated by pepscan. SRBD was in extended conformation in complex with ACE2 (PDB code 7DWY). FIG.5C is a graph of ANS fluorescence in buffer, in presence of SRBD, compound 1 and 1:1 complex of SRBD and compound 1. FIG.5D is a log plot of mean fluorescence intensity (MFI) as determined by flow cytometry of compound 1 on Tentagel® beads binding to biotin- SRBD under various denaturing conditions and labeled with streptavidin-AF647.

[0166] While the SAR studies suggest a dynamic binding mode, the melting point for compound 1 by differential scanning fluorimetry (DSF) is 45 degrees Celsius (C) which is similar for several of the hits identified from the screen and indicates some level of folded structure. DSF traces are fully reversible and activity is retained after heating andS1647.188.111 (SRI-230078-PCT) cooling of compound 1 which indicates that temperature induced unfolding is fully reversible. To assess the degree of Techneins® compound folding, 8-anilino-1- naphthalenesulfonic acid (ANS) fluorescence of compound 1 was measured (see FIG. 5C). ANS fluorescence indicated the presence of molten globule protein / polymer states versus random coil or stably folded states. ANS fluorescence was fully quenched in aqueous buffer and in the presence of SRBD which has a stable tertiary structure. Unbound compound 1 showed clear ANS fluorescence indicating a molten globule state in aqueous solution. Fluorescence is reduced on 1:1 binding with SRBD but not completely, suggesting that compound 1 retains a partial molten globule state on binding or that the combined Techneins® compound–SRBD binding interface does, which is consistent with a dynamic binding mode (see FIG.5C).

[0167] Various embodiments were directed to assessing the importance of molten globule structure for binding. In such embodiments, compound 1 synthesized on Tentagel® beads was treated with various denaturants and analyzed binding of labeled SRBD MFI in flow cytometry. Techneins® compounds were treated with denaturing agents bound native SRBD with the same affinity as untreated in all cases. However, when the Techneins® compounds and SRBD were both treated with denaturant striking, increases in binding were observed under certain conditions. Heating to 55 degrees C produced the greatest increase with >260-fold rise in MFI compared to native SRBD. Urea produced a >30 fold increase compared to native SRBD at both 4M and 8M denaturant concentrations. Guanidinium HCL showed some increase in binding (>3 fold) at 3M which was decreased at 6M concentration. In contrast, binding was reduced to background with sodium dodecyl sulfate (SDS) (see FIG.5D) and 1M NaCl (not shown). Notably, compound 1 did not bind to denatured BSA as a control, indicating the even binding of denatured SRBD is selective. Taken together, these results indicate that compound 1 binds to unfolded SRBD better than native SRBD and that denatured binding is largely mediated by hydrophobic and ionic interactions. This is consistent with a multivalent dynamic binding model which may be mutual between compound 1 and SRBD, where SRBD unfolds to some degree to also interact with the compounds. Equilibrium disruption of the protein tertiary structure exposes more hydrophobic and ionic contact points, favoring tighter binding to compounds. These findings align with the pepscan results that show, relative to monoclonal antibody binding, significant compound binding to many of the peptide segments which are not significantly solvent exposed in the crystal structure.S1647.188.111 (SRI-230078-PCT)

[0168] Potential of Techneins® compounds as therapeutics

[0169] The SAR studies for compound 1 showed that binding is synthetically optimizable (see FIGs.3A-3D) and specific for SARS-CoV-2 and its variants (see FIGs. 4A-4C and 5D). Competition of compound 1 with SRBD binding to hACE2 as measured by ELISA showed a 41% inhibition at 2 micromolar (µM) concertation of Techneins® compounds (see FIG.6A). The tighter binding scrambled sequence compound 11 showed 89% inhibition which further suggests that inhibition is synthetically optimizable in parallel with binding for this lead series. This indicates that compound 1 may be a good starting point for lead optimization as a viral entry inhibitor. Notably, no SRBD–hACE2 inhibition was observed for other structure-based peptide screening reports. Whether the mechanism of inhibition is due to direct competition with hACE2 binding, stabilization of the SRBD in the locked down inactive binding conformation, or even potentially due to destabilizing of the SRBD tertiary structure in mutual fuzzy binding with the compounds as suggested by the denaturation study remains to be determined. Given the strong affinity of these ligands, combination with a suitable warhead for targeting clearance by immunity or protein degradation may be alternative pathways to viral neutralization.

[0170] Compound 1 (SRI-89-8) exhibited excellent stability in human serum over extended periods of time with no significant degradation (see FIG.4A). In various experimental embodiments, pharmacokinetic (PK) properties were assessed in male and female C57BL / 6 mice in a single dose IV study (see FIG.6B) and showed species dependent half-life of 14 to 20 hours and long duration of action and exposure levels which would be advantageous for controlling viral replication and reducing viral load. Volume of distribution (Vss) indicates extensive tissue distribution and infiltration of compound 1 enabling access to viral reservoirs throughout the body. Overall, the PK properties are generally favorable for a compound targeting local and widely spread virus in the body, particularly considering the high affinity for the Techneins® compounds for the target.

[0171] FIGs.6A-6B illustrates the compound affinity to SRBD in mice. FIG.6A is a graph showing hACE2-captured SRBD with and without a Techneins® compound inhibitor. In particular, hACE2 (5 micrograms / milliliter (µg / mL) PBS) was coated on ELISA plate to react with SARS-CoV-2 SRBD in solution (1µg / mL) in the presence or absence of 2µM Techneins® compound inhibitor. The ACE2-bound SRBD was detected with a rabbit anti-SRBD antibody. Percent inhibition of SRBD binding toS1647.188.111 (SRI-230078-PCT) hACE2 is shown for compound 1 and scrambled sequence compound 11. FIG. 6B is a table showing PK properties of compound 1 following intravenous (IV) administration in male and female C57BL / 6 mice.

[0172] In accordance with various embodiment, compounds, referred to herein as Techneins® compounds, were identified as being affinity reagents to SARS-CoV-2 SRBD. The Techneins® compounds were affinity reagents that target the protein through a “fuzzy” binding mode that is synthetically accessible. In particular, the results indicated that affinity is primarily mediated through intrinsically disordered regions on the target proteins which suggests that Techneins® compounds may provide a novel chemical modality for targeting IDPs and intrinsically disordered regions on structured proteins. The SAR experimental embodiments presented here demonstrate the value of the mechanism of binding and validate the hit compound identified from screening. These findings also shed light on a novel medicinal chemistry path for optimization of both Techneins® compound and sequence.

[0173] The novel multivalent dynamic binding mode of these synthetically accessible Techneins® compounds presents an immediate advantage for selective broad-spectrum affinity over small molecules, peptides and monoclonal antibodies which generally rely on a highly structured binding site with tightly coordinated intermolecular interactions. Structured binding tends to be variant specific and loses activity against new strains as binding mutations arise. Techneins® compound binding, in contrast, is based on a dynamic selection of weak affinity contacts that when multiplied provide potent binding, and selectivity which is relatively resistant to mutational drift. Techneins® compounds thus provide a potentially more effective method for coping with drug affinity resistance as with SARS-CoV-2 variants.

[0174] Methods

[0175] Synthesis of Dhq building blocks. The procedure for synthesis of Fmoc DhqB- OH is described here as general example of Dhq building block synthesis.S1647.188.111 (SRI-230078-PCT) To a solution of Fmoc diaminopropane (preparation described below) (40 g, 120.18 mmol, 1.00 equiv, HCl) and compound m-pyridyl aldehyde (14.16 g, 132.20 mmol, 12.42 mL, 1.10 equiv) in toluene (1400 mL) were added MgSO4(101.27 g, 841.29 mmol, 7 equiv) and triethylamine (TEA) (18.24 g, 180.28 mmol, 25.09 mL, 1.50 equiv), then the mixture was added CH3COOH (577.36 mg, 9.61 mmol, 549.87 microliter (µL), 0.08 equiv), stirring at 20 to 30 degrees C for 36 hours.1HNMR(EB280-19-P1A) showed the most of starting material was consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was used for next step without further purification. Imine (49 g, crude) was obtained as a yellow solid.1H NMR: EB280-19-P1A, (400 megaHertz (MHz), CDCl3), δ ppm 1.70 - 1.88 (2 H, m) 3.15 - 3.35 (2 H, m) 3.49 - 3.69 (2 H, m) 4.04 - 4.19 (1 H, m) 4.30 (2 H, br d, J=7.00 Hz) 7.06 - 7.11 (1 H, m) 7.15 - 7.25 (4 H, m) 7.27 - 7.33 (2 H, m) 7.50 (2 H, d, J=7.38 Hz) 7.67 (2 H, d, J=7.50 Hz) 8.02 (1 H, dt, J=7.94, 1.72 Hz) 8.22 (1 H, s) 8.56 (1 H, dd, J=4.75, 1.63 Hz) 8.74 - 8.80 (1 H, m) 10.02 (1 H, s).

[0176] Homophthalic Anhydride (18.55 g, 114.41 mmol, 0.9 equiv) was added to a stirred solution of imine (49 g, 127.12 mmol, 1.00 equiv) in CH3COOH (282 mL) at 20 to 30 degrees C. Then the resulting mixture was further stirred at 120 degrees C for 4 hours. Liquid chromatography-mass spectrometry (LCMS) indicated compound homopthalic anhydride starting material was consumed completely. The mixture was concentrated in vacuo and diluted with EtOAc (286 mL). The organic solution was washed with 10% citric acid aqueous solution (3*286 mL), and brine 286 mL and dry with sodium sulfate, filtered and concentrated to give the residue. The crude product was purified by re-crystallization from (dichloromethane: methanol=3.5:0.5, 272 mL) at 20 to 30 degrees C for 45 minutes. Racemic Fmoc DhqB-OH (56 g, 100.22 mmol, 78.84% yield, 98% purity) was obtained as off-white solid confirmed by1HNMR(EB280-21-P1A), HPLC(EB280-21P1A), SFC(EB280-21-P1A).1H NMR: (400 MHz, Dimethyl sulfoxide (DMSO)- d6), δ ppm 1.61 - 1.81 (2 H, m) 2.86 - 2.92 (1 H,S1647.188.111 (SRI-230078-PCT) m) 3.04 (2 H, td, J=13.4, 6.82 Hertz (Hz)) 3.95 (1 H, br d, J=6.12 Hz) 4.20 - 4.24 (2 H, m) 4.27 - 4.32 (2 H, m) 5.47 (1 H, s) 7.23 - 7.34 (5 H, m) 7.37 - 7.41 (2 H, m) 7.42 - 7.46 (2 H, m) 7.61 - 7.71 (2 H, m) 7.88 (2 H, br d, J=7.50 Hz) 7.94 (1 H, dd, J=7.32, 1.44 Hz) 8.35 - 8.42 (2 H, m).

[0177] Racemic Fmoc DhqB-OH was separated into R,R and S,S enantiomers by preparative chiral SFC on an Agilent® 1260 equipped with a diode array detector (DAD) and Chiralpak® AD-3-3 µm 100*4.6mm I.D. column. The mobile phase was carbon dioxide and 0.05% diethanolamine (DEA) in ethanol at a flow rate of 2.8mL / minute. Gradient was 5% to 40% DEA / ethanol over 4.5 minutes.

[0178] Synthesis and purification of other Fmoc DhqX-OH building blocks and intermediates are described below.

[0179] Synthesis of Techneins® library. The Dhq combinatorial library was synthesized using “one-bead-one-compound” and “mix-and-split” methods of solid- phase synthesis. The library was constructed using 492 mg of TentaGel® amine resin (10 μm, loading = 0.25 mmol / g) with a possible diversity of 16.77 million compounds and 20 copies. For the synthesis of the Dhq library, the beads were swollen in dimethylformamide (DMF) / dichloromethane (DCM) (1:1, v / v) for 1 hour. Then, solvent was drained and the beads were suspended in DMF and divided evenly by pipet between eight plastic fritted syringes placed on a manifold. Then, eight different tetraptychs were constructed on the beads, a different tetraptych in each fritted syringe, by coupling first an L-amino acid–PAM ester followed by the coupling of a Dhq(x) building block, D- amino acid, or Glycine, according to the library design in FIG 2A.

[0180] Coupling Conditions for Fmoc–L-Amino Acid–PAM Esters in the Library Synthesis.3.5 equiv of Fmoc–L-amino acid–PAM ester was dissolved in a solution of 0.5 M Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU) in N- Methyl-2-pyrrolidone (NMP) (3.18 equiv of HATU). Then, N, N- Diisopropylethylamine (DIEA) (10 equiv) was added to this mixture to activate the amino acid for 30 seconds, and the solution was added to the resin and reacted for 30 minutes. After completion of the coupling reaction (confirmed by a ninhydrin test), the resin was drained and washed with DMF (3×5 mL).S1647.188.111 (SRI-230078-PCT)

[0181] Coupling Conditions for Fmoc–d-Amino Acid.5.5 equiv of Fmoc–d-amino acid was dissolved in a solution of 0.5M HATU in NMP (5 equiv of HATU). Then, DIEA (10 equiv) was added to this mixture to activate the amino acid for 30 seconds, and the solution was added to the resin and reacted for 30 minutes. After completion of the coupling reaction (confirmed by a ninhydrin test), the resin was drained and washed with DMF (3×5 mL).

[0182] Fmoc Deprotection. Fmoc deprotection was performed by the addition of 25% 4-methylpiperidine in DMF (5 mL) to the resin (1×5 minutes + 1×10 minutes), followed by draining and washing the resin with DMF (5×5 mL).

[0183] Allyl deprotection. After addition of the final tetraptych, the allyl protecting groups on select Dhq building blocks were cleaved using with Pd(PPh3)4and phenylsilane. To the resin was added 2 mL of anhydrous DCM, followed by the addition of phenylsilane (85 equiv) and Pd(PPh3)4 (1.5 equiv) solution in anhydrous DCM. The resin was then briefly gently agitated with argon and allowed to react for 20 minutes. The resin was then drained, washed with DCM, and then subjected to a second round of treatment with Pd(PPh3)4 and phenylsilane. The resin was then thoroughly washed with 0.5% (w / v) sodium diethyldithiocarbamate (DETC) in DMF, followed by washes with DMF and DCM (3x10 mL ea).

[0184] Global side chain deprotection. At the end of the library synthesis, the final Fmoc group was deprotected and the resin was treated with a solution of 95% (v / v) Trifluoroacetic acid (TFA), 2.5% (v / v) water, and 2.5% (v / v) triisopropylsilane (1 mL of cleavage solution per 10 mg of resin) for 2 hours at room temperature. Then, the TFA cocktail was drained, and the resin was thoroughly washed with DCM, DMF, DCM, and MeOH (3x10 mL ea).

[0185] Hit and Analog Synthesis. Hits were synthesized on ChemMatrix® Rink amide resin (loading 0.5 mmol / g, typical scale: 15 mg, 0.0075 mmol) by an automated peptide synthesizer (Biotage® Syro I) using standard Fmoc-based amide coupling conditions with diisopropylcarbodiimide (DIC) / Ethyl Cyano(hydroxyimino)acetate (Oxyma) as the coupling reagents. Fmoc-protected L-amino acid–PAM esters used in the library synthesis were replaced here by two separate residues: Fmoc–L-amino acid and Fmoc–S1647.188.111 (SRI-230078-PCT) PAM. The synthesis was performed using the following protocol: ChemMatrix® Rink amide resin was swollen in DCM for 1 hour, drained, washed with DMF, and placed on the peptide synthesizer for constructing the full sequence. Fmoc deprotection was performed by the addition of 25% 4-methylpiperidine in DMF (1.2 mL) to the resin (1×5 minutes + 1×10 minutes), followed by draining and washing the resin with DMF (5×1.2 mL). Couplings were performed by adding 250 μL of NMP to the resin followed by 90 μL of 0.25M Fmoc-protected amino acids (or Fmoc–PAM) in 0.25M Oxyma / DMF solution (3 equiv AA, 3 equiv Oxyma, 0.023 mmol) and 180 μL of 0.25 M DIC in DMF (6 equiv, 0.045 mmol). The resin mixture was allowed to react for 15 minutes at 60 degrees C and was then drained and washed with DMF (3×1.2 mL), and treated again with the same coupling conditions for double coupling. At the end of the double coupling, the Fmoc was deprotected, and these synthesis cycles were repeated on the peptide synthesizer until all of the residues were constructed onto the resin.

[0186] Manual addition of Fmoc-Gln(PEG3-Biotin)-OH and Fmoc-PEG12. Prior to automated synthesis, Fmoc-Gln(PEG3-Biotin)-OH and Fmoc-PEG12 were manually added to the resin (15 mg). The coupling reactions for the manual additions were monitored using the Kaiser ninhydrin test. The resin was first swelled for 1 hour in 1:1 (v / v) DMF / DCM, and Fmoc deprotection was carried out as described above. The resin was thoroughly washed with DMF, DCM, and NMP (3x5 mL ea). Then, a solution of Fmoc-Gln(PEG3-Biotin)-OH (5.5 equiv, 0.041 mmol) in 0.5M HCTU (5 equiv, 0.038 mmol), and DIEA (14.3 equiv, 0.107 mmol) was added to the resin. The reaction was carried out for 1 hour, and the resin was drained and washed with NMP, DCM, and DMF (3 x 5mL ea). Fmoc deprotection and subsequent resin washes was then carried out as described above. Then a solution of Fmoc-PEG12 (3.5 equiv, 0.026 mmol) in 0.5M HCTU (3.18 equiv, 0.024 mmol) and DIEA (10.0 equiv, 0.075 mmol) was added to the resin. The reaction was carried out for 1 hour, and the resin was drained and washed with NMP, DCM, and DMF (3x5 mL ea).

[0187] Allyl deprotection. After addition of the final tetraptych, the allyl protecting groups on select Dhq building blocks were cleaved using with Pd(PPh3)4 and phenylsilane. To the resin was added 2 mL of anhydrous DCM, followed by the addition of 79 µL of phenylsilane (85 equiv, 0.638 mmol) and 0.5 mL of Pd(PPh3)4(1.5 equiv, 0.011 mmol) solution in anhydrous DCM (26 mg / mL). The resin was then briefly gentlyS1647.188.111 (SRI-230078-PCT) agitated with argon and allowed to react for 20 minutes. The resin was then drained, washed with DCM, and then subjected to a second round of treatment with Pd(PPh3)4 and phenylsilane. The resin was then thoroughly washed with 0.5% (w / v) sodium diethyldithiocarbamate (DETC) in DMF (3x2 mL), followed by washes with DMF and DCM (3x10 mL ea).

[0188] Techneins® Compounds Cleavage. Cleavage from the solid support and side- chain deprotection were performed by the treatment of resin-Techneins® compound with a solution of 90% (v / v) TFA, 2.5% (v / v) water, and 2.5% (w / v) dithiothreitol (DTT), and 5% (v / v) triisopropylsilane (4 mL per 15 mg of resin) for 2 hours at room temperature. For biotinylated hits, NH4I (56 mg for 4 mL of cleavage cocktail). The TFA was then evaporated on a SpeedVac™ concentrator (Thermo Scientific® Savant SpeedVac™ concentrator) until the volume reached around 1 mL. The crude Techneins® compounds were then precipitated with chilled diethyl ether (3x15 mL) and centrifuged. The supernatant was decanted, yielding the crude Techneins® compounds as white solids. They were then purified by preparative LCMS.

[0189] Preparative LCMS purification. Resynthesized hits were purified on the Agilent® 1290 Infinity II Preparative LCMS system using a ZORBAX® 300SB-C18 column (21.2 mm×150 mm, 5 µm particle size) with a mobile phase of solvent A (0.1%TFA in water) and solvent B (0.1%TFA in 6:3:1 acetonitrile:isopropanol:water). Unless otherwise stated, the LC gradient used for the preparative purifications were 1% B for 5 minutes with a flow rate of 5 mL / minute, 1% to 40% B from 5.1 minutes to 10 minutes with a flow rate of 20 mL / minute, then 40% to 60% B for 20 minutes with a flow rate of 20 mL / minute.

[0190] Analytical LCMS analysis. All analytical LCMS analysis was carried out on a ThermoFisher® Fleet LCMS system using an Agilent® Pursuit 3 C18 column (50mm×2 mm, 3 µm particle size) with a mobile phase of solvent A (0.1% Formic acid in water). And solvent B (100% Acetonitrile). Unless otherwise stated, the LC gradient used for analytical LCMS analysis were 5% to 95%B for 8 minutes at a flow rate of 0.4 mL / minute.S1647.188.111 (SRI-230078-PCT)

[0191] Screening of Dhq Library against SARS-Cov2 SRBD on FAST. Screening of the Techneins® library against SARS-CoV-2 SRBD on FAST was conducted following a protocol similar to that previously described. Briefly, approximately 10 million 10-μm Techneins® library beads and 250,000 control beads were hydrated in buffer (11% PEG, 50 mM Tris, 1% BSA in phosphate-buffered saline (PBS)) for 30 minutes at room temperature with vortexing, followed by 1 minute of sonication to break apart large bead clumps. The hydrated beads were then centrifuged, and the bead pellets were washed twice with % BSA in PBS buffer. The bead suspension was further filtered through a 30 μm size cell strainer to remove bead aggregates. The concentration of the hydrated beads was determined based on bead counting using a hemocytometer. Aliquots of the bead suspension with the required number of beads were centrifuged and resuspended in blocking buffer (20% mouse serum, 0.5% Chaps, 200mM NaCl in PBS) and incubated overnight at room temperature with gentle rotation.

[0192] Following blocking, the beads were pelleted and resuspended in 1 mL of 2X blocking buffer (40% mouse serum, 1% Chaps, 400mM NaCl in PBS). This was then mixed at a 1:1 volume ratio with 1 mL of 600nM AF-555 conjugated SARS-CoV-2 SRBD and 1.2uM Cy5 conjugated mIgFc diluted in the same 2X blocking buffer. The probe / library bead mixture was incubated for 2 hours at room temperature with gentle rotation to allow the probe to bind to the library beads. After incubation, the beads were pelleted and unbound probes were aspirated, followed by three washes with 1 mL of wash buffer (1% mouse serum, 0.5% Chaps, 200 mM NaCl in PBS) for 5 minutes each, and an additional two washes with 1 mL of 0.5% Chaps / PBS. After the final centrifugation, the buffer was aspirated, leaving approximately 500 μL of residual buffer. The beads were sonicated for 30 seconds to dissociate newly formed bead clumps. Subsequently, 1.5 mL of prepared 0.3% low melting agarose (LMT) kept in a 37 degree C water bath was added to the re-sonicated beads to create the bead / soft agar suspension. The beads in the LMT suspension were then evenly plated onto FAST slides (screening plates), and the slides were placed on a cold tray to expedite curing and immobilization of the beads. Following gel formation, a layer of mounting medium (e.g., 500 μL Live-Cell medium) was gently applied on top of the gel to prevent rapid drying or fluorescence photo-quenching.

[0193] The sample slides were scanned and analyzed using the FAST system to identify hits. Hits were further analyzed with automated digital microscopy (ADM), and top hits were individually selected and isolated with a CellCelector™(Sartorius®) intoS1647.188.111 (SRI-230078-PCT) HPLC vials containing ddH2O for MS based sequencing. Table 1 below summarizes the results. Table 1

[0194] ELISA of hits and SAR analogs. Streptavidin-coated immunoassay microplates (ThermoFisher® Scientific) were rinsed three times with 200 μL / well of 1X PBS before use. Biotinylated Techneins® compounds were prepared to a final concentration of 1μM by sequential dilutions: first, the 1mM stock solution was diluted 1:200 with 2.5% DMSO-Phosphate buffered saline with Tween™ 20 (PBST), followed by another 1:5 dilution with 1% BSA. Next, 50 μL / well of the diluted biotinylated Techneins® compounds were added to the plate, and the plate was incubated at 4 degrees C overnight to allow the biotinylated Techneins® compounds to attach to the plate. The unbound Techneins® compounds were removed by washing the plates five times with 200 μL / well of PBST. The plates were then blocked by incubating with 100 μL / well of 1% BSA-PBST at room temperature for 1 hour. After blocking, 50 μL / well of SRBD- HRP (SignalChem®, diluted 1:5000 in 1% BSA-PBST) were added and incubated at 37 degrees C for 1 hour. The plate was washed with 200 μL / well of PBST five times to remove the unbound SRBD-HRP. The plates were then developed with substrate for 20 minutes and stopped by adding 50 μL / well of 2M H2S04. The OD at 40 nanometers (nm) was measured with a plate reader (SpectraMax®).

[0195] BLI. The Bio-layer interferometry assay was performed in Octet RED96e® (Sartorius®). High Precision Streptavidin (SAX) biosensors (Cat# 18-5117, Sartorius®) were used to capture 500nM of the Techneins® compounds, the loading step was set to achieve a maximum loading density of 2 nm shift. After loading the unloaded sites were blocked in 25 μg / mL Biocytin for 250 seconds. A baseline was measured for 120 seconds followed by association step for 600 seconds and dissociation steps for 800S1647.188.111 (SRI-230078-PCT) seconds. All the assay steps were carried out at 30 degrees C, in MOPS-TRIS buffer (20mM MOPS, 25mM KCl, 0.25mg / ml BSA, 0.02% Tween™, pH 8.0, the pH was adjusted using 1M Tris, pH 9.0). One unloaded sensor and a reference well without the analyte were used for reference subtraction. The data was analyzed via Octet® Data Analysis HT software (Ver.11.1.1.2.48), a 1:1 Langmuir binding fit model was used determine the KA (rate of association), KD (rate of dissociation) and the KD (affinity) values.

[0196] Pepscan by FACS. Fifteen overlapping 30-residue segments spanning the 240- amino acid SRBD protein (Arg319 to Lys558) were synthesized on TentaGel® beads. Approximately 5 million of each type of bead were hydrated, and single-bead suspensions were prepared as described in the “FAST screening” method.1 million beads of each peptide segment were resuspended in 100 μL of binding buffer (10mM 4- (2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) / 1% DMSO) and incubated with C-terminal tagged PEG12-biotin compound 1 at 1μM diluted in the same buffer. After incubation, the beads were washed three times with 1X PBST buffer, then stained again with 100 μL / sample streptavidin-AF647 (S32357, ThermoFisher® Scientific, diluted 1:400 with 1% BSA / PBS). The bead samples were then subjected to flow cytometry analysis (Symphony™ A3, BD Biosciences®), and the resulting MFI of AF647 data was analyzed by FlowJo™ software (TreeStar).

[0197] ANS assay. SARS-CoV-2 SRBD protein (200nM, Sino-Bio®) was preincubated with compound 1 (1μM) at room temperature for 1 hour. ANS (8-anilino- 1-naphthalenesulfonic acid, Sigma) was then added to the well, and the fluorescence of the ANS / SRBD with or without compound 1 was measured at room temperature on a spectrometer (SpectraMax®).

[0198] Binding in denaturing assay. Compound 1 was synthesized onto 10 μm TentaGel® beads. Single-bead suspension was prepared as in other sections.1 million beads / sample were resuspended in various denaturing solutions. The biotinylated SRBD (Sino-Bio®) was added to the beads / denaturing solution and incubated for 1 hour. The beads were then rinsed with 1 mL of the same denaturing solution and washed two more times with 1% BSA / PBS to remove unbound Bio-SRBD. The beads were further incubated with 100 μL / sample streptavidin-AF647 (S32357, ThermoFisher® Scientific,S1647.188.111 (SRI-230078-PCT) diluted 1:400 with 1% BSA / PBS). The bead samples were then subjected to flow cytometry analysis (Symphony™ A3, BD Biosciences®), and the resulting MFI of AF647 data was analyzed by FlowJo™ software (TreeStar).

[0199] Pharmacokinetic Studies. PK studies were conducted under NIAID contract. Male and female C57BL / 6 mice (4 in each group) were treated with a single dose administration on by the intravenous (iv) route via tail vein over 30 seconds with a vehicle at 0 mg / kilogram (kg) (Group 1), or compound 1 at 1 mg / kg (Group 2). Vehicle and Group 2 compound 1 were formulated in 50% PEG 400 / 20% DMSO / 30% sterile water. The dosing volume was 7.14 ml / kg. Animals were observed immediately following dose administration, once daily and prior to the last blood collection. Blood was collected from the retro-orbital sinus at 0.25, 1, 6, 24, 48, or 72 hours post-dose.

[0200] The blood samples were processed to plasma, and all collected samples were stored at ≤ -60 degrees C until analysis. A bioanalytical method was developed for compound 1 (SRI-89-8), with a lower limit of quantification (LLOQ) of 2.50 nanogram (ng) / mL in plasma. Group 2 animals had quantifiable concentrations of compound 1 through 72 hours after dose administration. Plasma concentrations of compound 1 were used to determine PK parameters.

[0201] Variants to compound 1 and assessment for SRBD binding

[0202] Various embodiments were directed to compounds that are variants of compound 1. Modifications were made to compound 1 and then the variants were assessed. The modifications included the addition of PEG12, addition of alpha Gal, biotinylation (e.g., addition of Biotin), changing the order of the pytchs, changing the order within pytch(s), randomizing the full sequence substitution of monomers, Gly substitutions at the N-terminal end of the Dhqs, Gly substitutions the C-terminal end of the Dhqs, Gly substitutions at both the N-terminal and C-terminal ends of the Dhqs, inversing the sequence, and enantiomer forms of the compound 1, among other modifications and combinations thereof. At least some of compounds 2-13 include variants of compound 1, which were further modified in experimental embodiments.

[0203] The variants included: d(Glu)-DhqO-Phe(4F)-PAM-d(Ala)-DhqY-Ser(OMe)-PAM-d(Ala)-DhqE- Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE-Ala-PAM-DhqF-d(Lys)-Val- PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-PEG12-Gln(PEG-Biotin)-S1647.188.111 (SRI-230078-PCT) CONH2(e.g., 17077-35-1, which included randomized ptych positions of the sequence of compound 1 and is a modified form of compound 8 including the addition of PEG12- Gln(PEG-Biotin); Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM-PEG12-Gln(PEG-Biotin)-CONH2 (e.g., 17077-35-2, which include randomization within each ptych of the sequence of compound 1 and is a modified form of compound 7 including the addition of PEG12- Gln(PEG-Biotin); Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2 (e.g., 17077-35-3, which included complete randomization of the sequence of compound 1 and is a modified form of compound 10 including the addition of PEG12-Gln(PEG- Biotin); PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2 (e.g., 17077-35-4, which included complete randomization of the sequence of compound 1 and is a modified form of compound 9 including the addition of PEG12- Gln(PEG-Biotin); Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin)-CONH2(e.g., 17077-35- 5, which included Gly substitutions on the N-terminal side of Dhqs of compound 1 and is a modified form of compound 3 including the addition of PEG12-Gln(PEG-Biotin); D(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM (e.g., 17077-35-6, which included Gly substitutions on the C- terminal side of Dhqs of compound 1 and is compound 5); Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM (e.g., 17077-35-7, which included Gly substitutions on the N-terminal and C- terminal sides of Dhqs of compound 1 and is compound 6);S1647.188.111 (SRI-230078-PCT) d(Ala)-PAM-Ala-PAM-d(Glu)-PAM-Phe(4F)-PAM-Gly-PAM-Phe(4F)-PAM- d(Ala)-PAM-Ser(OMe)-PAM-Gly-PAM-Ala(Cp)-PAM-d(Glu)-PAM-Ala-PAM-PAM- d(Lys)-Val-PAM-d(Ala)-PAM-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin) (e.g., 17077-35- 8, which included PAM substitutions for Dhqs from the sequence of compound 1 and is a modified form of compound 4 including the addition of PEG12-Gln(PEG-Biotin); PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala)-PEG12-Gln(PEG-Biotin) (e.g., 17077-35-9, which included inverse analog of the sequence of compound 1 and is a modified form of compound 12 including addition of PEG12-Gln(PEG-Biotin)); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin) (e.g., 76- 3, which included the addition of PEG12-Gln(PEG-Biotin) to the sequence of compound 1); d(Leu)-d(Pro)-d(Glu)-d(Ser)-Phe-PAM-d(Phe)-d(Glu)-d(Lys)-d(Arg)-Leu- PAM-Gly-d(Pro)-d(Arg)-d(Ser)-Phe-PAM-d(Tyr)-d(Thr)-d(Pro)-d(Arg)-Ala-PAM- d(Arg)-d(Phe)-d(Pro)-d(Val)-Gly-PAM-d(Leu)-d(Pro)-d(Arg)-d(Thr)-Gly-PAM-PEG12- Gln(Biotin)-CONH2 (e.g., 17077-35-10); PAM-d(Val)-PAM-d(Lys)-d(Pro)-d(Thr)-d(Pro)-PAM-d(Leu)-Phe-d(Thr)- d(Glu)-d(Pro)-Leu-d(Ser)-d(Pro)-d(Arg)-d(Phe)-d(Leu)-d(Arg)-PAM-d(Arg)-Gly-Phe- Gly-PAM-d(Arg)-d(Pro)-d(Arg)-Gly-d(Phe)-d(Ser)-PAM-Ala-d(Tyr)-d(Glu)-PEG12- Gln(Biotin)-CONH2(e.g., 17077-35-11, which included scrambling of the sequence of 17077-35-10); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Cys(alph-Gal)-CONH2(e.g., 17077-35-12, which included scrambling of the sequence and addition of PEG12- Cys(alpha-Gal)-CONH2 to the sequence of compound 1); PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12-Cys(alpha-Gal)-CONH2 (e.g., 17077-35-13, sometimes referred to as “77-3 alpha Gal” and which included scrambling of the sequence and addition of PEG12-Cys(alpha-Gal)-CONH2to theS1647.188.111 (SRI-230078-PCT) sequence of compound 1, and is a modified form of compound 11 including the addition of PEG12-Cys(alpha-Gal)-CONH2); PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12 (e.g., 17077-35-14, sometimes referred to as “77-4 alpha Gal negative, and which included scrambling of the sequence and addition of PEG12to the sequence of compound 1, and is a modified form of compound 11 including the addition of PEG12); and Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM- PEG12-Gln(PEG-Biotin) (e.g., 17077-52-18, which included the addition of PEG12- Gln(PEG-Biotin) to the sequence of compound 13).

[0204] The variants were formed and then an SA-plate for ELISA was used as described above to assess for SRBD binding. In particular, the Techneins® compounds were coated with: 1 µM ( 5% DMSO / 10nM HEPES / 0.05% Tween); SRBD: 5 ug / ml. Full-S: 10 µg / ml; Primary antibody (Ab): 1:1000; Secondary Ab: 1:3000.

[0205] FIG.7 illustrates data characterizing compound binding interaction with the SARS-CoV-2 spike receptor binding domain SRBD. All compounds had affinity to SRBD, with at least some having increased binding, such as with 17077-35-6, 17077- 35-7, and 77-4.

[0206] Compounds with affinity to fentanyl

[0207] In various embodiments, the above described Techneins® library was used to screen for affinity to fentanyl and the hits were selected and sequenced. The resulting synthetic compounds included: d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)-Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-1); d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-2);S1647.188.111 (SRI-230078-PCT) DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY-d( Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-3); d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)-Phe(4F)- PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-4); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-5); d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-6); d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM (e.g., 17107-91-7); DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM (e.g., 17107-91-8); DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-9); d(Ala)-DhresidueqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-10); DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-11); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-12); d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM (e.g., 17107-91-13);S1647.188.111 (SRI-230078-PCT) DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-14); D(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-15); d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM (e.g., 17107-91-16); d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM (e.g., 17107-91-17); d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM (e.g., 17107-91-18); d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-19); d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-20); d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM (e.g., 17107-91-21); DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17107-91-22); DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17107-91-23);S1647.188.111 (SRI-230078-PCT) d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM-Ala- DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108-1-1); d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM-DhqB- d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)-DhqO- Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-2); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-3); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)- CONH2(e.g., 17108-1-4); d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108- 1-5); DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108-1-6); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108-1-7); d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2(e.g., 17108-1-8); and d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2 (e.g., 17108-1-9).

[0208] FIGs.8A-8D data characterizing compound binding interaction with fentanyl, in accordance with various embodiments. In particular. FIGs.8A-8B are graphs showing the results of 500nM of the compounds exposed to fentanyl. FIGs.8C-8D areS1647.188.111 (SRI-230078-PCT) graphs showing the ELISA results from different concentrations of the compounds, including 1µM, 500nM, and 100nM.

[0209] Additional Information

[0210] FIG.9 is a table showing the physiochemical properties of biologically-active polymers as compared to the Dhq monomers. Physicochemical comparison between Dhqs and natural building blocks show general similarities except for increased organic properties such increased number of rings, increased lipophilicity and decreased heteroatom content. This leads to increased aggregate hydrophobicity in polymers of Dhqs which was balanced overall for aqueous solubility by combining with alpha amino acids.

[0211] Preparation of Fmoc, Boc diaminopropaneTo a solution of compound 1 (75 g, 430.44 mmol, 75.15 mL, 1.00 equiv) in tetrahydrofuran (THF) (750 mL) was added dropwise Na2CO3(136.87 g, 1.29 mol, 3 equiv) in H2O (750 mL) at below 15 degrees C in ice water bath, then Fmoc-Cl (111.36 g, 430.44 mmol, 1.00 equiv) was added dropwise, after the addition, the mixture was stirred at 20-30 degrees C for 30 minutes. TLC (Petroleum ether: Ethyl acetate= 3:1) indicated compound 1 was consumed completely. The two batches in parallel were merged. The mixture was quenched by addition ice water (1500 mL) at 0-30 degrees C, and then extracted with ethyl acetate (1500mL*3). The combined organic layers were washed with brine (1500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was re-crystallized with ethyl acetate (1200 mL) at 120 degrees C for 30 minutes. Compound 2 (315 g, 794.49 mmol, 92.29% yield) was obtained as a white solid confirmed by1NMR(EB280-12-P1A).1H NMR: EB280-12-P1A, (400 MHz, CDCl3), δ ppm 1.46 (9 H, s) 1.59 - 1.68 (2 H, m) 3.06 - 3.29 (4 H, m) 4.19 - 4.26 (1 H, m) 4.35 - 4.44 (1 H, m) 4.40 (1 H, br d, J=6.76 Hz) 4.86 (1 H, br s) 5.35 (1 H, br s) 7.29 - 7.34 (2 H, m) 7.38 - 7.43 (2 H, m) 7.61 (2 H, br d, J=7.38 Hz) 7.77 (2 H, d, J=7.50 Hz). LCMS : t =1.316 min, M-100+H : 297.1S1647.188.111 (SRI-230078-PCT)

[0212] Preparation of Fmoc diaminopropaneHCl was bubbled into EtOAc (4.00 M, 1500 mL, 13.2 equiv) at 0 degrees C for 1 hour to give a mixture. Then Compound 2 (180 g, 454 mmol, 1.00 equiv) in ethyl acetate (500 mL) was added to the reaction mixture. The reaction mixture was stirred at 20 degrees C for 1 hour. TLC (Plate 1, Petroleum ether: Ethyl acetate = 1: 1) showed the reaction was completed. The mixture was filtered and the filter cake was washed with 20.0 mL of ethyl acetate, dried in vacuum to give a white solid. Compound 3 (147 g, 441 mmol, 97.2% yield, HCl salt) was obtained as a white solid confirmed by HNMR (EB3744-4-P1A).1H NMR: 400 MHz, DMSO-d6. δ 8.04 - 7.84 (m, 5H), 7.72 - 7.63 (m, 2H), 7.47 - 7.39 (m, 3H), 7.37 - 7.29 (m, 2H), 4.37 - 4.28 (m, 2H), 4.26 - 4.17 (m, 1H), 3.12 - 3.00 (m, 2H), 2.83 - 2.69 (m, 2H), 1.76 - 1.63 (m, 2H).

[0213] Preparation of Fmoc diaminopropane m-pyrdyl imineTo a solution of compound 3 (40 g, 120.18 mmol, 1.00 equiv, HCl) and compound 3A (14.16 g, 132.20 mmol, 12.42 mL, 1.10 equiv) in toluene (1400 mL) were added MgSO4 (101.27 g, 841.29 mmol, 7 equiv) and TEA (18.24 g, 180.28 mmol, 25.09 mL, 1.50 equiv), then the mixture was added CH3COOH (577.36 mg, 9.61 mmol, 549.87 µL, 0.08 equiv), stirring at 20-30 degrees C for 36 hours.1HNMR(EB280-19-P1A) showed the most of starting material was consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was used for next step without further purification. Compound 4 (49 g, crude) was obtained as a yellow solid.1H NMR: (400 MHz, CDCl3), δ ppm 1.70 - 1.88 (2 H, m) 3.15 - 3.35 (2 H, m) 3.49 - 3.69 (2 H, m) 4.04 - 4.19 (1 H, m) 4.30 (2 H, br d, J=7.00 Hz) 7.06 - 7.11 (1 H, m) 7.15 - 7.25 (4 H, m) 7.27 - 7.33 (2 H, m) 7.50 (2 H, d, J=7.38 Hz) 7.67 (2 H, d, J=7.50 Hz) 8.02 (1 H, dt, J=7.94, 1.72 Hz) 8.22 (1 H, s) 8.56 (1 H, dd, J=4.75, 1.63 Hz) 8.74 - 8.80 (1 H, m) 10.02 (1 H, s).S1647.188.111 (SRI-230078-PCT)

[0214] Preparation of Fmoc DhqB-OHAs noted above, Compound 4A (18.55 g, 114.41 mmol, 0.9 equiv) was added to a stirred solution of compound 4 (49 g, 127.12 mmol, 1.00 equiv) in CH3COOH (282 mL) at 20-30 degrees C. Then the resulting mixture was further stirred at 120 degrees C for 4 hours. LCMS(EB280-21-P1A) indicated compound 4 was consumed completely. The mixture was concentrated in vacuo and diluted with EtOAc (286 mL). The organic solution was washed with 10% citric acid aqueous solution (3*286 mL), and brine 286 mL and dried with sodium sulfate, filtered and concentrated to give the residue. The crude product was purified by re-crystallization from (dichloromethane: methanol=3.5:0.5, 272 mL) at 20-30 degrees C for 45 minutes. Target 1 (56 g, 100.22 mmol, 78.84% yield, 98% purity) was obtained as off-white solid confirmed by1HNMR(EB280-21-P1A), HPLC(EB280-21-P1A), SFC(EB280-21-P1A).1H NMR: (400 MHz, DMSO- d6),1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 - 1.81 (2 H, m) 2.86 - 2.92 (1 H, m) 3.04 (2 H, td, J=13.4, 6.82 Hz) 3.95 (1 H, br d, J=6.12 Hz) 4.20 - 4.24 (2 H, m) 4.27 - 4.32 (2 H, m) 5.47 (1 H, s) 7.23 - 7.34 (5 H, m) 7.37 - 7.41 (2 H, m) 7.42 - 7.46 (2 H, m) 7.61 - 7.71 (2 H, m) 7.88 (2 H, br d, J=7.50 Hz) 7.94 (1 H, dd, J=7.32, 1.44 Hz) 8.35 - 8.42 (2 H, m). LCMS : t =1.160 min, M+H : 548.2.

[0215] Preparation of Fmoc diaminopropane phenyl imineTo a solution of compound 2 (90.0 g, 270.4 mmol, 33.3 µL, 1.00 equiv, HCl) and compound 2B (31.5 g, 297.4 mmol, 30.0 mL, 1.10 equiv) in CHCl3(2500 mL) were added MgSO4 (227.8 g, 1.89 mol, 7.00 equiv) and TEA (41.0 g, 405.6 mmol, 56.4 mL,S1647.188.111 (SRI-230078-PCT) 1.50 equiv). Then to the mixture was added CH3COOH (1.30 g, 21.6 mmol, 1.24 mL, 0.08 equiv). The reaction was stirred at 20-30 degrees C for 36 hours under N2. HNMR (EB348-5-P1A) showed the most starting material was consumed. The mixture was filtered and the filtrate was concentrated in vacuum to give a crude product. No purification to give compound 4 (136.6 g, crude) as off-white solid.1H NMR: 400 MHz, CHLOROFORM-d 1.75 - 1.88 (m, 2 H) 2.97 (q, J=7.34 Hz, 7 H) 3.29 (q, J=5.88 Hz, 2 H) 3.60 (br t, J=5.94 Hz, 2 H) 4.02 - 4.18 (m, 1 H) 4.25 (br d, J=7.12 Hz, 2 H) 5.67 (br s, 1 H) 7.11 - 7.24 (m, 3 H) 7.24 - 7.36 (m, 6 H) 7.50 (d, J=7.50 Hz, 2 H) 7.65 (br d, J=7.62 Hz, 5 H) 8.19 (s, 1 H).

[0216] Preparation of FMOC DhqF-OHTo a solution of compound 4 (104 g, 270.5 mmol, 1.00 equiv) in CH3COOH (1300 mL) was added compound 4A (39.4 g, 243.4 mmol, 0.90 equiv). The reaction was stirred at 120-130 degrees C for 4 hours. LCMS (EB348-6-P1A) showed the reaction was completed. The mixture was concentrated under reduced pressure to give a crude product. To the mixture was added 1300 mL Ethyl acetate. The resulting mixture was washed with 3900 mL 10% citric acid aqueous solution (1300mL*3). The combined organic layers were dried over anhydrous Na2SO4, then filtered and the filtrate was concentrated in vacuum to give a crude product. The crude product was purified by silica gel column chromatography (Ethyl acetate: Petroleum ether=3:1; Dichloromethane: Methanol=30:1) to give Target 4 (53.0 g, 96.1 mmol, 35.5% yield, 99.2% purity) as off-white solid confirmed by HNMR (EB348-6-P1A), HPLC (EB348- 6-P1A) and SFC (EB348-6-P1_D12), SFC (EB348-6-P1-D3). LCMS: t =1.281 min, M+H: 547.31H NMR: (400 MHz, DMSO-d6), 1.56 - 1.83 (m, 1 H) 1.56 - 1.83 (m, 1 H) 2.73 - 2.88 (m, 1 H) 2.89 - 3.15 (m, 2 H) 3.93 - 4.06 (m, 2 H) 4.14 (s, 1 H) 4.17 - 4.24 (m, 1 H) 4.26 - 4.33 (m, 2 H) 5.36 (s, 1 H) 5.75 (s, 1 H) 7.07 (br d, J=7.38 Hz, 2 H) 7.13S1647.188.111 (SRI-230078-PCT) - 7.35 (m, 7 H) 7.35 - 7.47 (m, 4 H) 7.68 (br d, J=7.26 Hz, 2 H) 7.88 (br d, J=7.60 Hz, 2 H) 7.92 - 7.96 (m, 1 H) 7.92 - 7.97 (m, 1 H).

[0217] Preparation of p(proprionic acid) benzaldehydeTo a solution of HOOCH (281.15 g, 5.85 mol, 230 mL, 7.85 equiv) was added Et3N (248.95 g, 2.46 mol, 342.44 mL, 3.3 equiv) at 0 degrees C followed by compound 6 (100 g, 745.54 mmol, 1 equiv) and compound 6A (107.45 g, 745.54 mmol, 1 equiv). At the end of the addition, the mixture was stirred at 100 degrees C for 12 hours. TLC (plate1 Petroleum ether: Ethyl acetate) indicated reactant 1 was consumed completely. The mixture was added 1071 ml ice water, and then the resulting mixture was adjusted to pH = 1 with HCl solution (2 mol / L). The water layer was extracted with Ethyl acetate (1071ml * 3), the combined organic layers were washed with brine 1071 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with Petroleum ether: Ethyl acetate (2:1, 642 ml) at 20-30 degrees C for 30 minutes. Compound 7 (102 g, crude) was obtained as a yellow solid confirmed by1HNMR(EB280-24-P1A).1H NMR: (400 MHz, DMSO- d6), δ ppm 2.61 (2 H, t, J=7.60 Hz) 2.94 (2 H, t, J=7.60 Hz) 7.48 (2 H, d, J=8.00 Hz) 7.84 (2 H, d, J=8.00 Hz) 9.97 (1 H, s).

[0218] Preparation of p(allylproprionate) benzaldehydeTo a suspension of K2CO3(387.82 g, 2.81 mol, 5 equiv) in THF (1.2 L) were added compound 7 (100 g, 561.22 mmol, 1.0 equiv) and compound 7A (64.50 g, 533.16 mmol, 0.95 equiv). After the addition, the mixture was stirred at 50 degrees C under N2 for 16 hours. TLC (plate1 Petroleum ether: Ethyl acetate = 1:1 Rf= 0.27) indicated reactant 1S1647.188.111 (SRI-230078-PCT) was consumed completely. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was used for next step without further purification. Compound 8 (64 g, crude) was obtained as a colorless oil confirmed by1HNMR(EB280-25-P1A).1H NMR: EB280-25-P1A, (400 MHz, DMSO- d6),1H NMR (400 MHz, DMSO-d6) δ ppm 2.69 - 2.76 (2 H, m) 2.93 - 3.00 (2 H, m) 4.53 (2 H, dt, J=5.44, 1.34 Hz) 5.16 - 5.29 (2 H, m) 5.81 - 5.94 (1 H, m) 7.47 (2 H, d, J=8.00 Hz) 7.82 (2 H, d, J=8.00 Hz) 9.96 (1 H, s).

[0219] Preparation of Fmoc diaminopropane p(allyproprionate) benzyl imineTo a solution of compound 3 (88.73 g, 266.59 mmol, 1.00 equiv, HCl) in toluene (880 mL) was added Et3N (40.46 g, 399.88 mmol, 55.66 mL, 1.50 equiv) and MgSO4 (224.62 g, 1.87 mol, 7.00 equiv). After 10 minutes, compound 8 (64 g, 293.24 mmol, 1.1 equiv) and CH3COOH (1.28 g, 21.33 mmol, 1.22 mL, 0.08 equiv) were added. After the addition, the mixture was stirred at 20-30 degrees C for 16 hours.1HNMR(EB280-26- P1A) showed the most of starting material was consumed. The mixture was concentrated under reduced pressure. The residue was used for next step without further purification. Compound 9 (95.0 g, crude) was obtained as off-white solid.1H NMR: EB280-26-P1A, (400 MHz, CDCl3), δ ppm 1.65 - 1.87 (2 H, m) 2.42 - 2.64 (3 H, m) 2.84 - 2.99 (2 H, m) 3.13 - 3.36 (2 H, m) 3.44 - 3.64 (2 H, m) 4.06 - 4.16 (1 H, m) 4.22 - 4.38 (2 H, m) 5.08 - 5.24 (3 H, m) 5.71 - 5.87 (1 H, m) 7.10 - 7.21 (4 H, m) 7.23 - 7.33 (3 H, m) 7.49 (2 H, d, J=7.26 Hz) 7.53 - 7.60 (2 H, m) 7.63 - 7.68 (2 H, m) 7.71 (1 H, d, J=8.12 Hz) 8.15 (1 H, s) 9.87 (1 H, s).S1647.188.111 (SRI-230078-PCT)

[0220] Preparation of Fmoc DhqE-OHTo a solution of compound 9 (95.0 g, 191.30 mmol, 1.00 equiv) in CH3COOH (950 mL) was added compound 4A (31.02 g, 191.30 mmol, 1.00 equiv). After the addition, the mixture was stirred at 120 degrees C for 6 hours. LCMS(EB280-27-P1A) indicated reactant 1 was consumed completely. The reaction mixture was concentrated under reduced pressure to give brown gum, then diluted with EtOAc(950 mL), washed organic layer with aq.citric acid (10%, 600 mL x3), then washed with brine (600 mL), dried over Na2SO4, concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Dichloromethane: Methanol = 100: 3). TLC (plate1 Dichloromethane: Methanol = 10:1, Rf= 0.27). Target 5 (57.0 g, 86.53 mmol, 45.23% yield) was obtained as off-white solid confirmed by SFC(EB280-27-P1A). LCMS : t =1.342 min, M+H : 659.3

[0221] Preparation of p(allyloxy) benzaldehyde51.8% To a solution of compound 1 (90.0 g, 737 mmol, 1.00 equiv) in acetone (900 mL) was added compound 1A (135 g, 1.12 mol, 1.51 equiv) and K2CO3 (153 g, 1.11 mol, 1.50 equiv). The mixture was stirred at 70 degrees C for 16 hours. TLC (Petroleum ether: Ethyl acetate= 5: 1, Rf= 0.51) indicated Reactant 1 was consumed, and one major was detected. The reaction mixture was concentrated under reduced pressure, and then diluted with H2O 600 mL and extracted with Ethyl acetate 1200 mL (600 mL*2). The combined organic layers were washed with brine 600 mL (300 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 2 (62.0 g, crude) was obtained as yellow oil and was used for next step directly.S1647.188.111 (SRI-230078-PCT)

[0222] Preparation of Fmoc diaminopropane p(allyloxy) benzy iminecrude To a solution of compound 2 (121 g, 364 mmol, 1.00 equiv, HCl) in toluene (1300 mL) was added TEA (111 g, 1.09 mol, 152 mL, 3.00 equiv) and stirred at 25 degrees C for 30 minutes. Then CH3COOH (1.75 g, 29.12 mmol, 1.67 mL, 0.08 equiv), compound 2A (65.0 g, 401 mmol, 1.10 equiv) and MgSO4(307 g, 2.55 mol, 7.00 equiv) was added, and the mixture was stirred at 25 degrees C for 16 hours. TLC (Dichloromethane: Methanol= 10: 1, Rf = 0.5) indicated Reactant 2 was consumed completely and two new spots formed. The reaction mixture was filtered and concentrated in vacuum to give a yellow oil (48.0 g, crude). The crude product was used directly for next step without further purification.

[0223] Preparation of Fmoc DhqY-OH50.0 g, 95% To a solution of compound 3A (43.1 g, 266 mmol, 0.90 equiv) in CH3COOH (754 mL) was added compound 3 (130 g, 295 mmol, 1.00 equiv) at 25 degrees C. The mixture was stirred at 130 degrees C for 16 hours. TLC (Dichloromethane: Methanol=10: 1, Rf = 0.5) indicated Reactant 3 was consumed completely. The reaction mixture was concentrated under reduced pressure to give brown gum, then diluted with Ethyl acetate (1000 mL), washed organic layer with aq.citric acid (10%, 500 mL*3), then washed with brine (1000 mL), dried over Na2SO4, concentrated under reduced pressure to give crude product. The residue was purified by column chromatography (SiO2, Dichloromethane: Methanol= 10: 1). Compound Target 3 (83.0 g, 135 mmol, 45.7%S1647.188.111 (SRI-230078-PCT) yield, 98.0% purity) was obtained as a white solid.1HNMR: (400 MHz, CDCl3) δ = 8.18 - 8.01 (m, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.56 (br t, J = 7.8 Hz, 2H), 7.40 - 7.30 (m, 4H), 7.29 - 7.25 (m, 2H), 7.09 - 7.05 (m, 1H), 6.89 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 6.04 - 5.93 (m, 2H), 5.35 (dd, J = 1.5, 17.3 Hz, 1H), 5.25 (dd, J = 1.3, 10.5 Hz, 1H), 5.18 (s, 1H), 4.42 (d, J = 5.3 Hz, 2H), 4.35 - 4.29 (m, 1H), 4.24 (br t, J = 7.9 Hz, 2H), 4.12 - 4.07 (m, 1H), 3.80 (s, 1H), 3.38 - 3.32 (m, 2H), 3.03 (br dd, J = 6.8, 13.1 Hz, 1H), 2.73 - 2.64 (m, 1H), 1.97 - 1.86 (m, 1H), 1.66 (br dd, J = 3.1, 10.3 Hz, 1H).

[0224] Preparation of Fmoc diamonpropane m(phenol ether) benzyl imineTo a solution of Compound 1 (45.0 g, 135 mmol, 1.00 equiv, HCl) and Compound 1A (29.4 g, 148 mmol, 2.85 mL, 1.10 equiv) in CHCl3(1575 mL) were added MgSO4(113 g, 946 mmol, 7.00 equiv) and TEA (20.5 g, 202 mmol, 28.2 mL, 1.50 equiv), then the mixture was added CH3COOH (649 mg, 10.8 mmol, 618 µL, 0.08 equiv), stirring at 50 degrees C for 60 hours. HNMR(EB3744-13-P1A2) showed the most of starting material was consumed. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was used for next step without further purification. Compound 2 (103 g, crude) was obtained as a yellow solid.1H NMR: 400 MHz, CHLOROFORM-d. δ = 9.91 - 9.86 (m, 1H), 8.20 - 8.12 (m, 1H), 7.73 - 7.64 (m, 2H), 7.55 - 7.48 (m, 2H).S1647.188.111 (SRI-230078-PCT) Compound 2A (20.4 g, 126 mmol, 5.83e-1 equiv) was added to a stirred solution of Compound 2 (103, 216 mmol, 1.00 equiv) in CH3COOH (300 mL) at 20 degrees C. Then the resulting mixture was further stirred at 120 degrees C for 12 hours. LCMS (EB3744-16-P1L1) indicated reactant 1 was consumed completely. The mixture was concentrated in vacuo and diluted with EtOAc (300 ml). The organic solution was washed with 10% citric acid aqueous solution (3*300 mL), and brine (300 mL) and dried with sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (DCM:(THF: MeOH = 1 / 1) =12%-14%) to give yellow oil. Target 2 (57.0 g, 86.3 mmol, 39.9% yield, 96.8% purity) was obtained as a yellow oil confirmed by LCMS(EB3744-16-P1L5).1H NMR: 400 MHz, dmso-d6.

[0226] X-ray Crystallography of Fmoc-DhqB Monomer. X-ray quality crystals were grown from a saturated 1,2-dichloroethane / ethanol / methanol solution that was allowed to slowly evaporate over 48 hours to deposit the crystal diffracted. A colorless plate 0.100 x 0.100 x 0.030 mm in size was mounted on a Cryoloop with Paratone oil. Data was collected in a nitrogen gas stream at 100(2) K using phi and omega scans. Crystal- to-detector distance was 60 mm and exposure time was 10 seconds per frame using a scan width of 2.0°. Data collection was 99.5% complete to 67.000° in θ. A total of 74213 reflections were collected covering the indices, -5<=h<=8, -19<=k<=19, - 25<=l<=25.4836 reflections were found to be symmetrical independent, with an Rint of 0.0325. Indexing and unit cell refinement indicated a primitive, monoclinic lattice. The space group was found to be P 21 / c (No.14). The data was integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by iterative methods (SHELXT) produced a complete heavy-atom phasing model consistent with the proposed structure. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014.

[0227] Screening. As previously described, from screening 20 hits were sequenced out of 38 selected beads. There were resynthesized and purified to >95% purity by RP- HLPC and characterized by LCMS. Hits were resynthesized as the naked and C- terminal biotinylated analogues for immobilization in ELISA and BLI as describedS1647.188.111 (SRI-230078-PCT) above. As only 10 million beads were screened in the library of 16.7 million library size no hit redundancy was observed. MST binding of the hits to SRBD confirmed 12 hits as positive reproducible binders. Subsequent ELISA assay was used to measure relative potency of binding which lead us to select SRI-89-8 as a candidate.

[0228] Specificity of SRI-89-8. In addition to selectivity screening against SARS-CoV- 2 variants and negative control glycoproteins described above, various embodiments were directed to assessing binding selectivity in cells expressing Spike protein on their surface. S1 spike protein fused with orange fluorescent protein (OFP) was expressed in HEK293 cells with expression levels and location confirmed by orange fluorescent protein (OFP). Biotinylated Techneins® compound was bound to Alexa 647 labeled streptavidin and then incubated with S1 expressing cells and control HEK293 not expressing S1. Selective binding of labeled SRI-89-8 to the surface of the S1 expressing cells was observed compared to no binding to control cells. This further demonstrated specific binding of Techneins® compound to target protein on a cell surface in a cell melieu in serum.

[0229] FIGs.10A-10B show the results for assessing selectivity in cells expressing Spike protein. FIG.10A includes images of wild-type HEK293 cells (left) and Spike expressing HEK293 cells (right). Biotinylated compounds were incubated with SA-647 and then added to the cells. S1 is the full-length protein and was fused with OFP. As shown in FIG.10A, the synthetic compounds (yellow) showed high specificity to cells with spike expressed on their surface (purple, right) but not to cells without S1 expressed (blue, left), FIG.10B are images of the wild-type HEK293 cells (top) and S1+ expressing wild-type HEK293 cells (bottom).

[0230] Evaluating Techneins thermal stability by DSF. DSF experiments were carried out using the commercially available Protein thermal Shift™ Dye kit from Applied Biosystems® (catalog number 4461146). Data was collected and analyzed using a ViiA 7 Real-Time PCR System. The protocol was carried out per the manufacturer instructions. All measurements were performed in triplicate and conducted at a final Techneins® compound concentration of 62.5uM. Briefly, 12.5uL solution of 100 µM Techneins® compound stock solution (in water or HEPES buffer) were diluted with 2.5uL of 8X Protein Thermal Shift™ Dye stock solution and 5uL of Protein Thermal Shift™ Buffer, resulting in a final volume of 20uL per PCR well. Lysozyme (5mg / mL)S1647.188.111 (SRI-230078-PCT) in MilliQ water was used as a control. A 2-step temperature gradient of 1.6C / s starting at 25 degrees C for 2 minutes in the first step followed by 0.05C / s at 99 degrees C over 2 minutes in the second step was utilized for these experiments. The resultant thermal shift profiles for each Techneins® compound were directly analyzed using the a ViiA 7 Real-Time PCR instrument software.

[0231] FIG.11 is a graph of the melting curve plot for compound 1. Melting point curves of the compound 1 (e.g., SRI-89-8) showed a transition at 45 degrees C (e.g., a melt temperature) which was repeated over three heating and cooling cycles indicating that folding / unfolding is reversible.

[0232] Pepscan with Neutralizing Antibody. Neutralizing antibody (SARS-CoV-2 spike, 2019-nCoV, Sino Bio) shows a similar binding profile to SRI-89-8 in a pepscan of the SRBD region but is 100 fold less intense by MFI suggesting much weaker binding.

[0233] Other applications. Embodiments are not limited to targets of SARs-CoV-2 and fentanyl, and the Techneins® library can be used to screen for other purposes. In some embodiments, other target proteins were screened for to identify affinity reagents. The targets included IL-6 and K-Ras. Table 2 below summarizes example results of the screening: Table 2S1647.188.111 (SRI-230078-PCT)S1647.188.111 (SRI-230078-PCT)

[0234] Although specific embodiments have been illustrated and described herein, a variety of alternate and / or equivalent implementations can be substituted for the specific embodiments shown and described without departing from the scope of the present disclosure. This application is intended to cover any adaptations or variations of the specific embodiments discussed herein.

Claims

S1647.188.111 (SRI-230078) CLAIMS 1. A synthetic compound comprising at least one dihydroisoquinolinone (Dhq) monomer having a structure of:wherein: X is selected from C and N; and each R1 and R2 are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof, wherein the compound is selected from: d(Glu)-DhqO-Phe(4F)-phenyl-acetamido-methylene (PAM)-d(Ala)-DhqY- Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE- Ala-PAM-DhqF-d(Lys)-Val-PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- PEG12-Gln(PEG-Biotin)-CONH2; Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin)-CONH2; d(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM;S1647.188.111 (SRI-230078) Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM; PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala)-PEG12-Gln(PEG-Biotin); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-(L)Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Cys(alph-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12-Cys(alpha-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12; Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM- PEG12-Gln(PEG-Biotin); d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)-Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM;S1647.188.111 (SRI-230078) d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)- Phe(4F)-PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM; DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM-d(Lys)- DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY-d(Glu)- Phe-PAM-DhqE-Gly-Phe(4F)-PAM; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(-Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM;S1647.188.111 (SRI-230078) DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val- PAM-DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqE-Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala-DhqE-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM-PEG12-Gln(Biotin)-CONH2;S1647.188.111 (SRI-230078) d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM- Ala-DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)- DhqY-Ala(Cp)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)- DhqO-Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)- CONH2; d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; and d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2.

2. The synthetic compound of claim 1, wherein the at least one Dhq monomer includes:S1647.188.111 (SRI-230078).

3. The synthetic compound of claim 1, wherein the synthetic compound is configured to bind to a spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or to fentanyl.

4. The synthetic compound of claim 1, wherein DhqB, DhqE, DhqF, DhqO, and DhqY include:

5. The synthetic compound of claim 1, wherein Ala(Cp), Phe(4F), and Ser(OMe) include: NH NH(Fmoc-Ala(Cp)), (Fmoc-Phe(4F)), andS1647.188.111 (SRI-230078) Fmoc-NH O C MeO OH (Fmoc-Ser(OMe)).

6. A synthetic compound comprising at least one dihydroisoquinolinone (Dhq) monomer, wherein the compound is selected from: d(Glu)-DhqO-Phe(4F)-phenyl-acetamido-methylene (PAM)-d(Ala)-DhqY- Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Ala)-DhqE- Ala-PAM-DhqF-d(Lys)-Val-PAM-Gly-DhqY-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- PEG12-Gln(PEG-Biotin)-CONH2; Ala-d(Ala)-DhqE-PAM-DhqO-Phe(4F)-d(Glu)-PAM-DhqY-Phe(4F)-Gly-PAM- DhqY-Ser(OMe)-d(Ala)-PAM-Ala(Cp)-Gly-DhqB-PAM-DhqB-Ala-d(Glu)-PAM- d(Lys)-Val-DhqF-PAM-Ala(Cp)-d(Ala)-DhqE-PAM-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqO-PAM-Ala-DhqY-DhqE-d(Glu)-PAM-Ala(Cp)-Phe(4F)-d(Lys)-PAM- d(Glu)-PAM-PAM-Gly-Ser(OMe)-Val-Ala-Ala(Cp)-PAM-DhqE-d(Ala)-PAM-d(Ala)- DhqB-PAM-DhqY-DhqF-DhqB-Phe(4F)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; PAM-Ser(OMe)-Phe(4F)-DhqB-DhqF-d(Lys)-PAM-DhqE-Ala-DhqY-d(Glu)- PAM-DhqO-Phe(4F)-Ala-PAM-DhqB-d(Ala)-PAM-Gly-PAM-Ala(Cp)-DhqY-PAM- d(Ala)-Gly-PAM-DhqE-Ala(Cp)-Val-d(Glu)-d(Ala)-PEG12-Gln(PEG-Biotin)-CONH2; Gly-DhqE-Ala-PAM-Gly-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM-Gly- DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Ala-PAM-DhqF-d(Lys)- Val-PAM-Gly-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin)-CONH2; d(Ala)-DhqE-Gly-PAM-d(Glu)-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-d(Ala)- DhqY-Gly-PAM-Gly-DhqB-Gly-PAM-d(Glu)-DhqB-Gly-PAM-DhqF-Gly-Val-PAM- d(Ala)-DhqE-Gly-PAM; Gly-DhqE-Gly-PAM-Gly-DhqO-Gly-PAM-Gly-DhqY-Gly-PAM-Gly-DhqY- Gly-PAM-Gly-DhqB-Gly-PAM-Gly-DhqB-Gly-PAM-DhqF-Gly-Gly-PAM-Gly-DhqE- Gly-PAM; PAM-Ala(Cp)-DhqE-d(Ala)-PAM-Val-d(Lys)-DhqF-PAM-Ala-DhqB-d(Glu)- PAM-Ala(Cp)-DhqB-Gly-PAM-Ser(OMe)-DhqY-d(Ala)-PAM-Phe(4F)-DhqY-Gly- PAM-Phe(4F)-DhqO-d(Glu)-PAM-Ala-DhqE-d(Ala)-PEG12-Gln(PEG-Biotin);S1647.188.111 (SRI-230078) d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(PEG-Biotin); d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM- DhqF-d(Lys)-(L)Val-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Cys(alph-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12-Cys(alpha-Gal)-CONH2; PAM-Ala(Cp)-DhqE-DhqY-d(Ala)-Ala(Cp)-Val-d(Ala)-PAM-Phe(4F)-PAM- Gly-PAM-DhqO-Ala-DhqB-PAM-PAM-d(Glu)-DhqY-PAM-Ala-Gly-PAM-DhqB- d(Ala)-DhqE-d(Glu)-Phe(4F)-DhqF-d(Lys)-Ser(OMe)-PEG12; and Ala-(+)DhqE-d(Ala)-PAM-Glu-(+)DhqO-d(Phe(4F))-PAM-Gly-(+)DhqY- d(Phe(4F))-PAM-Ala-(+)DhqY-d(Ser(OMe))-PAM-Gly-(+)DhqB-d(Ala(Cp))-PAM- Glu-(+)DhqB-d(Ala)-PAM-(+)DhqF-Lys-d(Val)-PAM-Ala-(+)DhqE-d(Ala(Cp))-PAM- PEG12-Gln(PEG-Biotin).

7. The synthetic compound of claim 6, wherein DhqB, DhqE, DhqF, DhqO, and DhqY include:S1647.188.111 (SRI-230078) 8. The synthetic compound of claim 6, wherein Ala(Cp), Phe(4F), and Ser(OMe) include: NH NH(Fmoc-Ala(Cp)),(Fmoc-Phe(4F)), and NH(Fmoc-Ser(OMe)).

9. The synthetic compound of claim 6, wherein the synthetic compound is configured to bind to a spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

10. A synthetic compound comprising: a plurality of dihydroisoquinolinone (Dhq) monomers having a structure of:wherein: X is selected from C and N; and each R1and R2are independently selected from H, O, phenyl, allyl, alkenyl, carbonyl, and a combination thereof; a plurality of amino acid monomers selected from: l-α-amino acids, d-α-amino acids, and non-natural amino acids of Ala(Cp), Phe(4F), Ser(OMe); and cleavable groups between at least portions of the plurality of Dhq monomers and the plurality of amino acid monomers, wherein the synthetic compound is configured to bind to fentanyl.S1647.188.111 (SRI-230078) 11. The synthetic compound of claim 10, wherein each of the plurality of Dhq monomers have a structure of:.

12. The synthetic compound of claim 10, wherein the synthetic compound includes: a plurality of molecules, each of the plurality of molecules including a subset of the plurality of Dhq monomers and the plurality of amino acid monomers and the cleavable groups between each of the plurality of molecules.

13. The synthetic compound of claim 12, wherein the synthetic compound includes eight molecules, each of the eight molecules including three monomers including one of the plurality of Dhq monomers and two of the plurality of the amino acid monomers, and one of the cleavable groups coupled to one of the three monomers.

14. The synthetic compound of claim 10, wherein the plurality of amino acid monomers are selected from l-α-amino acids, d-α-amino acids, and non-natural amino acids including: Ala(Cp), Phe(4F), Ser(OMe), Ala, Gly, Phe, Val, d(Ala), d(Gly), d(Glu), and d(Lys).

15. The synthetic compound of claim 10, wherein each R1 and R2 are independently selected from H, phenol, O-allyl, and (CH2)2-COO-allyl.

16. The synthetic compound of claim 10, wherein R1 includes:

17. The synthetic compound of claim 10, wherein R2includes:S1647.188.111 (SRI-230078)18. The synthetic compound of claim 10, wherein each of the plurality of Dhq monomers includes a structure selected from:

19. The synthetic compound of claim 10, wherein each of the plurality of Dhq monomers includes a selected from:S1647.188.111 (SRI-230078)20. The synthetic compound of claim 10, wherein the synthetic compound is selected from: d(Glu)-DhqB-Ala-phenyl-acetamido-methylene (PAM)-d(Glu)-DhqB- Ser(OMe)-PAM-DhqE-d(Lys)-Ala(Cp)-PAM-d(Lys)-DhqE-Val-PAM-DhqO-d(Glu)- Val-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqO-d(Lys)-Phe(4F)-PAM-Gly-DhqB-Gly- PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Lys)-DhqE-Ser(OMe)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM- d(Lys)-DhqF-Phe-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Ala-PAM-Gly-DhqY-Phe(4F)-PAM- d(Lys)-DhqE-Val-PAM-DhqY-d(Glu)-Ser(OMe)-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqO-d(Lys)-Phe-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqF-d(Ala)- Phe(4F)-PAM-DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM;S1647.188.111 (SRI-230078) d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM-d(Ala)- DhqO-Gly-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqB-Gly-Ala-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-Gly-Val-PAM-DhqY- d(Glu)-Phe-PAM-DhqY-d(Lys)-Ser(OMe)-PAM; DhqO-d(Lys)-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Lys)-DhqE-Ser(OMe)- PAM-d(Ala)-DhqY-Ser(OMe)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)- Ser(OMe)-PAM-DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-Gly-Phe-PAM-d(Lys)- DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-d(Ala)-Gly-PAM-DhqY-d(Glu)- Phe-PAM-DhqE-Gly-Phe(4F)-PAM; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-d(Glu)-Ala-PAM- DhqF-d(-Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-Gly-DhqB-Phe-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Glu)-Ala-PAM-d(Ala)- DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; d(Ala)-DhqE-Ala-PAM-Gly-DhqO-Val-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqF-Ala-PAM-DhqE-d(Ala)-Gly-PAM-DhqY- d(Glu)-Phe-PAM-Gly-DhqY-Ala-PAM; DhqB-d(Ala)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- d(Ala)-DhqE-Phe(4F)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Gly-PAM;S1647.188.111 (SRI-230078) d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Glu)-Ala-PAM- d(Ala)-DhqE-Phe(4F)-PAM-d(Glu)-DhqE-Phe-PAM-d(Glu)-DhqF-Gly-PAM-DhqY- d(Glu)-Phe-PAM-d(Lys)-DhqE-Phe-PAM; d(Glu)-DhqB-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-DhqE-d(Lys)-Ala(Cp)- PAM-DhqF-d(Ala)-Phe-PAM-DhqB-d(Glu)-Phe(4F)-PAM-d(Glu)-DhqB-Ala-PAM- DhqY-d(Glu)-Phe-PAM-DhqE-Gly-Phe(4F)-PAM; d(Glu)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqF-d(Ala)-Phe(4F)-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqB-Gly-PAM; d(Glu)-DhqE-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-d(Glu)-DhqB-Val- PAM-DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqE-Gly-Ser(OMe)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqF-d(Ala)-Ala-PAM-d(Glu)-DhqB-Val-PAM-DhqB- d(Glu)-Gly-PAM-DhqE-d(Lys)-Ala-PAM-DhqF-d(Ala)-Phe(4F)-PAM-d(Glu)-DhqY- Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM; d(Glu)-DhqE-Ala-PAM-DhqY-Gly-Gly-PAM-d(Glu)-DhqB-Val-PAM-d(Ala)- DhqY-Ser(OMe)-PAM-d(Glu)-DhqE-Phe-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-DhqE- Gly-Ser(OMe)-PAM-d(Ala-DhqE-Ala(Cp)-PAM; DhqE-Gly-Ala-PAM-DhqB-d(Ala)-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-Gly-DhqB-Phe-PAM-DhqE- Gly-Ser(OMe)-PAM-DhqY-Gly-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; DhqE-Gly-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-DhqF-d(Lys)-Gly-PAM- DhqB-Gly-Ala-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqB-Ala-PAM-DhqE-Gly- Ser(OMe)-PAM-DhqY-d(Lys)-Ser(OMe)-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DHQB-d(Ala)-Ala(Cp)-PAM-DhqE-Gly-Phe-PAM- Ala-DhqE-Phe(4F)-PAM-DhqE-d(Lys)-Ala-PAM-DhqE-d(Ala)-Gly-PAM-d(Glu)- DhqY-Ala(Cp)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Ala)-DhqE-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-DhqE-Gly-Phe-PAM- DhqB-d(Glu)-Gly-PAM-d(Lys)-DhqF-Ala-PAM-DhqB-d(Ala)-Ser(OMe)-PAM-d(Ala)- DhqO-Gly-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2;S1647.188.111 (SRI-230078) d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Lys)-DhqE-Val-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-d(Glu)-DhqB-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)- PAM-DhqB-d(Glu)-Gly-PAM-DhqB-d(Glu)-Phe(4F)-PAM-DhqB-d(Ala)-Ser(OMe)- PAM-d(Glu)-DhqY-Ala(Cp)-PAM-d(Ala)-DhqE-Ala(Cp)-PAM-PEG12-Gln(Biotin)- CONH2; d(Glu)-DhqB-Ala-PAM-DhqB-Ala-Ala(Cp)-PAM-d(Glu)-DhqB-Val-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- d(Ala)-DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; DhqO-d(Lys)-Ala-PAM-Gly-DhqF-Ser(OMe)-PAM-Gly-DhqY-Phe(4F)-PAM- d(Ala)-DhqY-Ser(OMe)-PAM-Gly-DhqB-Ala(Cp)-PAM-d(Glu)-DhqF-Gly-PAM- DhqE-Gly-Ser(OMe)-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Ala)-DhqE-Ala-PAM-d(Glu)-DhqO-Phe(4F)-PAM-DhqE-Gly-Phe-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Glu)-DhqE-Phe-PAM-DhqE-Gly-Val-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqY-Ala-PAM-PEG12-Gln(Biotin)-CONH2; d(Glu)-DhqB-Ala-PAM-DhqY-Gly-Gly-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- d(Ala)-DhqE-Phe(4F)-PAM-Gly-DhqB-Ala(Cp)-PAM-DhqB-d(Ala)-Ser(OMe)-PAM- DhqY-d(Glu)-Phe-PAM-Gly-DhqB-Ala(Cp)-PAM-PEG12-Gln(Biotin)-CONH2; and d(Glu)-DhqB-Ala-PAM-DhqF-Ala-Ala-PAM-DhqE-d(Lys)-Ala(Cp)-PAM- DhqF-d(Glu)-Ala(Cp)-PAM-d(Lys)-DhqE-Gly-PAM-DhqE-d(Ala)-Gly-PAM-d(Ala)- DhqO-Gly-PAM-Gly-DhqB-Gly-PAM-PEG12-Gln(Biotin)-CONH2, wherein DhqB, DhqE, DhqF, DhqO, and DhqY include five different Dhq monomers, each having the structure.

21. The synthetic compound of claim 20, wherein DhqB, DhqE, DhqF, DhqO, and DhqY include:S1647.188.111 (SRI-230078)22. The synthetic compound of claim 20, wherein Ala(Cp), Phe(4F), and Ser(OMe) include: NH NH(Fmoc-Ala(Cp)), (Fmoc-Phe(4F)), and Fmoc-NH O C MeO OH (Fmoc-Ser(OMe)).

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