Registry of Antiviral Compound Libraries

Introduction

The INTREPID Alliance Antiviral Development Landscape highlights many gaps in small molecule antiviral treatments for the 13 priority viral families of pandemic concern as identified by the World Health Organization.¹ Indeed, for some priority viral families there are no clinical or preclinical molecules in development. Small molecule antivirals are key tools in our preparedness arsenal. They provide scalable, accessible solutions that can save lives and reduce the potential devastating consequences of future epidemics and pandemics. By connecting researchers to the available resources that enable the discovery and development of new antivirals, we aim to address the existing gaps that threaten our global health security.²

The discovery process typically starts by screening compound libraries to identify chemical starting points for optimization into new drugs. INTREPID has created a listing of promising, accessible compound libraries for antiviral screening that collectively form the INTREPID Alliance Registry of Antiviral Compound Libraries. INTREPID surveyed compound libraries that have been publicly disclosed across academic institutions, corporate, and commercial vendors, to identify the most appropriate libraries for inclusion in the broader INTREPID Registry. Some of the criteria that were used in the selection process included access through collaboration agreements, minimal costs, and minimal other non-financial obligations, relevance of the compound content for antiviral discovery, and size of the library. INTREPID recommends these libraries for consideration by antiviral R&D scientists interested in accelerating efforts to discover new antivirals.

Each of the individual compound libraries in the Registry were organized into 4 categories as shown in Table 1. Descriptions of each of the 4 categories and the individual libraries contained within each category can be accessed using the links embedded in the table.

A special thanks to these organizations for agreeing to be listed as a resource.

Table 1. The INTREPID Alliance Registry of Antiviral Compound Libraries^*

Library Source	Categories Click on a category or library name below to explore more
	Drug Repurposing Libraries	Direct-Acting Antiviral Libraries	Privileged Chemical Structure-Based Libraries	Novel Compound Screening Libraries
The Broad Institute	Drug Repurposing Hub ▼	-	-	-
Calibr-Skaggs Scripps Research	ReFRAME Library ▼	Antivirals in ReFRAME Library ▼	-	-
CD3 & VirusBank Platform KU Leuven	KURE Repurposing Compound Library ▼	Vi-KURE ▼	-	Diverse Compound Library (350K compounds) ▼
National Center for Advancing Translational Sciences (NCATS) NIH	NCATS Pharmaceutical Collection ▼	-	-	NCATS Artificial Intelligence Diversity Library ▼ NCATS Genesis Chemical Library ▼
Commercial Vendors	Approved and Investigational Drugs ▼	-	Nucleosides Protease Inhibitors Peptidomimetics Macrocycles Metal-binding motifs ▼	Fragments Diversity Libraries ▼

Drug Repurposing Libraries

Libraries of regulatory approved drugs and compounds that have been previously investigated in Phase 1-3 clinical trials are often referred to as drug repurposing libraries. Remdesivir, the first drug approved to treat COVID-19, was previously evaluated in clinical trials towards Ebola and therefore was likely a component of many existing comprehensive drug repurposing libraries prior to the COVID-19 pandemic.³ Consequently, screening of a drug repurposing library is a powerful and proven way to accelerate the discovery of new drugs for viral diseases and arguably one of the best approaches towards meeting the 100 Days Mission for small molecule compounds.

Drug repurposing libraries are available from multiple sources including many commercial vendors and academic/non-profit institutions. The compound numbers in these libraries vary, ranging from several hundred compounds to >10,000 compounds. Although many commercial drug repurposing libraries are available, several prominent collections are accessible to the broader research community through collaboration.

The Drug Repurposing Libraries are alphabetically listed below and include brief descriptions of each library along with references, websites, and website navigational tips.

The Broad Institute Drug Repurposing Hub

Calibr-Skaggs, Scripps Research ReFRAME Library

KURE - KU Leuven Repurposing Compound Library (CD3, Virusbank Platform)

NCATS Pharmaceutical Collection (NPC)

Commercial-Sourced Drug Repurposing Libraries

Almost all commercial vendors of compound libraries, readily identified through online searches, market drug repurposing libraries (approved and clinical drugs) of one description or another. These libraries can range in size from hundreds to thousands of compounds and therefore differ substantially in their content and scope. Interested researchers are encouraged to review the information provided by the commercial vendors as to the suitability of the collections for their individual screening purposes.

Direct-Acting Antiviral Libraries

Direct-acting antiviral (DAA) libraries contain molecules that have confirmed molecular interactions towards a viral protein, or likely interactions based on chemical structure related to other known DAAs. The value of screening specific direct-acting antiviral libraries is readily apparent when considering the origins of the first small molecule COVID-19 treatments. Remdesivir and Molnupiravir were previously reported as broad-spectrum antivirals prior to COVID-19, and Nirmatrelvir was the result of optimization from a SARS-CoV-1 inhibitor, previously discovered for the 2002 SARS epidemic.^4,5,6 Moreover, DAAs due to their optimization towards a viral target, may have limited interactions with host targets and accordingly reduced safety risks. Screening preclinical and clinical DAAs can therefore accelerate the discovery of new DAAs for pandemic preparedness viruses. Although INTREPID concludes that DAA libraries are highly valuable libraries, no specific DAA-only libraries are publicly available at this time. For access to collections of direct-acting antivirals researchers are recommended to consider the Drug Repurposing Libraries category.

Below is a listing of drug repurposing libraries with significant numbers of direct-acting antivirals.

Calibr-Skaggs Scripps Research ReFRAME Library

Vi-KURE – Viral KU Leuven Repurposing Compound Library (CD3, Virusbank Platform)

Privileged Chemical Structure-Based Libraries

Certain chemical classes of compounds tend to be privileged as antiviral treatments, for example, nucleoside analogs and protease inhibitors. Indeed, herpes viruses, HIV, Hepatitis B and C, and now COVID-19 all have FDA approved drugs that are nucleoside analogs.⁷ Therefore, it is important to consider screening privileged chemical structure libraries that may be better suited towards the discovery of novel antivirals within the proven classes of antiviral drugs. Novel leads identified from these screens may have greater probability of clinical success based on the established precedent for these classes of chemotypes.

The type of libraries recommended for antiviral screening by INTREPID include but are not limited to: Nucleoside and Nucleotide Analogs; Protease Inhibitor Libraries; Peptidomimetics, Macrocycles and Metal-binding Motifs. The chemical leads identified through screening these libraries typically require considerable medicinal chemistry optimization that results in extended timelines before clinical development can begin. However, they are a good supplement to the screening of DAAs and drug repurposing libraries to identify promising chemical starting points.

Commercial-Sourced Privileged Chemical Structure-Based Libraries

Many of the commercial vendors market chemical structure-based libraries that range in size from a thousand to >10,000 compounds; examples to consider include Nucleoside and Nucleotide Analogs; Protease Inhibitor Libraries (covalent and non-covalent), Peptidomimetics, Macrocycles, and Metal-binding Motifs. In some cases, vendors also describe the availability of antiviral libraries that are based on the chemical structures of known antivirals. These chemical structure-based libraries are expected to be valuable sources of new leads for pandemic preparedness. Interested researchers are advised to conduct their own analysis of the commercial vendor collections as to their suitability for screening.

Source (Alphabetical)	Library Name	Compound Number**
APExBIO www.apexbt.com	DiscoveryProbe™ Protease Inhibitor Library	825
Asinex www.asinex.com	Purine-based Nucleosides	240
	Pyrimidine-based Nucleosides	240
	Nucleoside Mimetics	3,826
	Macrocycles	10,091
	Peptidomimetics	9,144
	α-helix mimetics	6,867
	Covalent Inhibitor Pre-Plated	972
	Metal Chelate	1,794
	Antiviral Library	6,827
ChemDiv www.chemdiv.com	Purine Based Nucleoside Mimetics	1,300
	Nucleoside Mimetics	2,600
	Cysteine Proteases Inhibitors	9,144
	Macrocycles	2,335
	Peptidomimetic	36,711
Enamine www.enamine.net	Nucleoside Mimetics	320
	Macrocycles	1,952
	Antiviral Library (nucleoside-like cpds)	3,200
	Cysteine-Focused Covalent	3,200
MedChemExpress www.medchemexpress.com	Cysteine-Protease Focused Covalent	2,000
	Cysteine Protease Focused	9,000
SelleckChem www.selleckchem.com	Nucleoside Analogue	228
	Macrocyclic Compound	184
	Protease Inhibitor	454

Novel Compound Screening Libraries

The screening of diverse collections of novel compounds which have no known pharmacological activity, remains a worthwhile endeavor for pandemic preparedness despite the longer timelines required to identify a clinical compound. Novel compound libraries can include just a few hundred compounds (e.g., fragment libraries, many tens of thousands of compounds; chemical diversity libraries, or billions of compounds; DNA-encoded libraries (DELs)). The goal of these screening library collections is to generate a novel (previously unidentified), chemical starting point for medicinal chemistry optimization so in most cases the new chemical matter is expected to have favorable intellectual property potential. In our view, the best novel compound libraries are those that have been carefully curated so that their content permits a broad range of chemical space to be covered. Large libraries (>10,000 cpds) are generally only available through commercial vendors, with only a few listings of readily accessible libraries for pandemic preparedness screening.

Diverse Compound Library

NCATS Artificial Intelligence Diversity (AID) Library

NCATS Genesis Chemical Library

Commercial-Sourced Novel Compound Screening Libraries

Almost all commercial library vendors list novel, pharmacologically untested compounds. In general, aside from the fragment libraries, the libraries in this category are large (>10,000 compounds) and therefore, high-throughput screening capabilities are needed which can be challenging in a BSL3/4 environment. Diversity compound collections that are designed to efficiently map chemical space and only contain compounds with drug-like properties are preferred. Interested researchers are advised to review and conduct their own diligence and cost analysis on commercially available novel compound libraries.

Source (Alphabetical)	Library Name	Compound Number***
Asinex www.asinex.com	Asinex Fragments	20,061
	Diversity Pre-plated Set	119,877
	Diversity-2 Pre-plated Set	282,478
ChemDiv www.chemdiv.com	Soluble Diversity	15,500
	SMART™	55,000
	Fragments	11,269
Enamine www.enamine.net	Discovery Diversity Set	10,240
	Discovery Diversity Set	50,240
	High-fidelity Fragment	1,920
	3D Shape Diverse Fragment	1,200
MedChemExpress www.medchemexpress.com	50K Diversity	50,000
	3D Diverse Fragment	5,400
	5K Scaffold Library	5,000
SelleckChem www.selleckchem.com	Fragment Library	1,015
	HTS Library for Drug Discovery	99,008

Conclusion

The INTREPID Alliance Registry of Antiviral Compound Libraries has been created to focus future antiviral screening efforts and help accelerate the drug discovery process for pandemic preparedness. The Antiviral Compound Registry primarily includes drug repurposing libraries that contain varying numbers of direct-acting antivirals, and other collections of importance for antiviral drug discovery. Many of the non-commercial compound collections are readily accessible to organizations across the globe through collaboration agreements.

We found no purposefully built, comprehensive library of preclinical and clinical direct-acting antivirals to include in the listing. Based on the small molecule approvals for COVID-19, an open access collection of direct-acting antivirals would be a valuable addition to the library.

INTREPID also welcomes information about additional compound collections to improve our listing. Send us a message through our online form.

On occasion, antiviral compounds get shelved within different organizations for financial, business, or other reasons. These compounds often have inherent value, serving as tool compounds or potential leads for future antiviral programs.

Some of the libraries listed in our registry will consider the submission of new compounds, that meet certain criteria, into their existing libraries. Establishing contact with these institutions to potentially adopt promising antiviral compounds is encouraged.

The institutions that may accept compounds include:

Calibr-Skaggs, Scripps Research: https://reframedb.org/

KURE - KU Leuven Repurposing Compound Library (CD3): https://www.cd3.be/about-cd3