Curious Discoveries in Antiviral Drug Development: The Role of Serendipity

Abstract

Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2'-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses.

Innovative methods in health information behaviour research

“…Although serendipity has featured in the literature of both Information Science and Health Science, with renewed interest (Forrester, 2019;Shneiderman, 2019), it is not often a focus in studies of information behaviour. The health literature reveals many potential subjects for health information behaviour researchers, and for further assessment of the instrument, e.g., serendipity in drug discoveries, diseases and dysfunctions (De Clercq, 2015;Goldstein et al, 2019;Michelucci, 2019).…”

A compendium of small molecule direct-acting and host-targeting inhibitors as therapies against alphaviruses

“…Since then, research on suramin has gained momentum after its anticancer and antiviral potential was discovered between the 1970s and 1990s. 76,77 Its antiviral activity against CHIKV, SFV and SINV was recently demonstrated. 78,79 Suramin restricted CHIKV multiplication via inhibition of CHIKV RNA synthesis.…”

An improved synthesis of adefovir and related analogues

“…The acyclic nucleoside phosphonate adefovir ( 1 ) [1], administered as its dipivoxil prodrug form ( 2 ) [2], is used clinically for the treatment of infections caused by the hepatitis B virus (HBV) [3–5] and the herpes simplex virus (HSV, Fig. 1) [5–6]. While 1 possesses inhibitory activity against the human immunodeficiency virus (HIV) [1,5], it has not been approved by the FDA for the treatment of HIV as the dose required to elicit inhibition can cause nephrotoxicity [7].…”